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1.
Int J Neuropsychopharmacol ; 24(3): 191-199, 2021 03 17.
Artículo en Inglés | MEDLINE | ID: mdl-33125470

RESUMEN

BACKGROUND: The serotonin transporter gene (SLC6A4; 5-HTT; SERT) is considered a prime candidate in pharmacogenetic research in major depressive disorder (MDD). Besides genetic variation, recent advances have spotlighted the involvement of epigenetic mechanisms such as DNA methylation in predicting antidepressant treatment response in "pharmaco-epigenetic" approaches. In MDD, lower SLC6A4 promoter methylation has been suggested to predict impaired response to serotonergic antidepressants. The present study sought to replicate and extend this finding in a large, independent sample of MDD patients. METHODS: The sample comprised n = 236 Caucasian patients with MDD receiving antidepressant medication in a naturalistic treatment setting. Functional DNA methylation of 9 CpG sites located in the SLC6A4 promoter region was analyzed via direct sequencing of sodium bisulfite- treated DNA extracted from blood cells. Patients were assessed over the course of a 6-week in-patient treatment using the Hamilton Depression Scale (HAM-D). RESULTS: Results confirm relative SLC6A4 hypomethylation to predict impaired antidepressant response both dimensionally and categorically (HAM-D reductions < 50%) and to furthermore be indicative of nonremission (HAM-D > 7). This also held true in a homogenous subgroup of patients continuously treated with selective serotonin reuptake inhibitors or serotonin/noradrenaline reuptake inhibitors (n = 110). CONCLUSIONS: Impaired response to serotonergic antidepressants via SLC6A4 hypomethylation may be conveyed by increased gene expression and consequently decreased serotonin availability, which may counteract the effects of serotonergic antidepressants. The present results could in the future inform clinical decision-making towards a more personalized treatment of MDD.


Asunto(s)
Antidepresivos/farmacología , Metilación de ADN/genética , Trastorno Depresivo Mayor/tratamiento farmacológico , Trastorno Depresivo Mayor/genética , Proteínas de Transporte de Serotonina en la Membrana Plasmática/genética , Adulto , Anciano , Islas de CpG , Femenino , Humanos , Masculino , Persona de Mediana Edad , Farmacogenética , Pruebas de Farmacogenómica , Regiones Promotoras Genéticas
2.
Transl Psychiatry ; 8(1): 226, 2018 10 19.
Artículo en Inglés | MEDLINE | ID: mdl-30341278

RESUMEN

Increased sympathetic noradrenergic signaling is crucially involved in fear and anxiety as defensive states. MicroRNAs regulate dynamic gene expression during synaptic plasticity and genetic variation of microRNAs modulating noradrenaline transporter gene (SLC6A2) expression may thus lead to altered central and peripheral processing of fear and anxiety. In silico prediction of microRNA regulation of SLC6A2 was confirmed by luciferase reporter assays and identified hsa-miR-579-3p as a regulating microRNA. The minor (T)-allele of rs2910931 (MAFcases = 0.431, MAFcontrols = 0.368) upstream of MIR579 was associated with panic disorder in patients (pallelic = 0.004, ncases = 506, ncontrols = 506) and with higher trait anxiety in healthy individuals (pASI = 0.029, pACQ = 0.047, n = 3112). Compared to the major (A)-allele, increased promoter activity was observed in luciferase reporter assays in vitro suggesting more effective MIR579 expression and SLC6A2 repression in vivo (p = 0.041). Healthy individuals carrying at least one (T)-allele showed a brain activation pattern suggesting increased defensive responding and sympathetic noradrenergic activation in midbrain and limbic areas during the extinction of conditioned fear. Panic disorder patients carrying two (T)-alleles showed elevated heart rates in an anxiety-provoking behavioral avoidance test (F(2, 270) = 5.47, p = 0.005). Fine-tuning of noradrenaline homeostasis by a MIR579 genetic variation modulated central and peripheral sympathetic noradrenergic activation during fear processing and anxiety. This study opens new perspectives on the role of microRNAs in the etiopathogenesis of anxiety disorders, particularly their cardiovascular symptoms and comorbidities.


Asunto(s)
Encéfalo/metabolismo , Miedo/fisiología , Regulación de la Expresión Génica , MicroARNs/metabolismo , Proteínas de Transporte de Noradrenalina a través de la Membrana Plasmática/metabolismo , Norepinefrina/fisiología , Trastorno de Pánico/metabolismo , Sistema Nervioso Simpático/fisiopatología , Adulto , Alelos , Ansiedad/genética , Ansiedad/metabolismo , Encéfalo/fisiopatología , Mapeo Encefálico , Condicionamiento Clásico , Extinción Psicológica , Femenino , Variación Genética , Humanos , Imagen por Resonancia Magnética , Masculino , MicroARNs/genética , Proteínas de Transporte de Noradrenalina a través de la Membrana Plasmática/genética , Trastorno de Pánico/genética , Trastorno de Pánico/fisiopatología , Polimorfismo de Nucleótido Simple , Regulación hacia Arriba
3.
Nervenarzt ; 89(3): 239-240, 2018 03.
Artículo en Alemán | MEDLINE | ID: mdl-29411051

Asunto(s)
Psicoterapia , Humanos
4.
Nervenarzt ; 89(1): 99-112, 2018 Jan.
Artículo en Alemán | MEDLINE | ID: mdl-28932896

RESUMEN

Autoimmune encephalitis is a group of autoimmune inflammatory disorders affecting both grey and white matter of the central nervous system. Encephalitis with autoantibodies against the N­methyl-D-aspartate receptor (NMDA-R) is the most frequent autoimmune encephalitis syndrome presenting with a characteristic sequence of psychiatric and neurological symptoms. Treatment necessitates a close interdisciplinary cooperation. This article provides an update on the current knowledge on diagnostic standards, pathogenesis, and treatment strategies for anti-NMDA-R encephalitis from psychiatric and neurological perspectives.


Asunto(s)
Encefalitis Antirreceptor N-Metil-D-Aspartato/inmunología , Encefalitis Antirreceptor N-Metil-D-Aspartato/terapia , Autoanticuerpos/sangre , Receptores de N-Metil-D-Aspartato/inmunología , Encefalitis Antirreceptor N-Metil-D-Aspartato/diagnóstico , Encefalitis Antirreceptor N-Metil-D-Aspartato/psicología , Trastornos del Conocimiento/diagnóstico , Trastornos del Conocimiento/inmunología , Trastornos del Conocimiento/psicología , Trastornos del Conocimiento/terapia , Diagnóstico Diferencial , Femenino , Humanos , Comunicación Interdisciplinaria , Colaboración Intersectorial , Masculino , Trastornos Mentales/diagnóstico , Trastornos Mentales/inmunología , Trastornos Mentales/psicología , Trastornos Mentales/terapia , Neuralgia Posherpética/diagnóstico , Neuralgia Posherpética/inmunología , Neuralgia Posherpética/psicología , Neuralgia Posherpética/terapia , Neoplasias Ováricas/diagnóstico , Neoplasias Ováricas/inmunología , Neoplasias Ováricas/terapia , Síndromes Paraneoplásicos/diagnóstico , Síndromes Paraneoplásicos/inmunología , Síndromes Paraneoplásicos/psicología , Síndromes Paraneoplásicos/terapia , Pronóstico , Teratoma/inmunología , Adulto Joven
5.
J Neural Transm (Vienna) ; 125(2): 229-238, 2018 02.
Artículo en Inglés | MEDLINE | ID: mdl-29159580

RESUMEN

The amygdala plays a crucial role in the pathogenesis of major depressive disorder (MDD). While robust findings support a negative impact of illness duration on hippocampal volume in MDD, morphometric studies of the amygdala have yielded inhomogeneous results. Considering the methodical problems of automatic segmentation methods, a standardized segmentation protocol with proven inter- and intra-rater reliability was employed using high-resolution magnetic resonance imaging. To identify the effect of MDD on amygdala morphometry, 23 unipolar depressed patients who responded to antidepressant medication and 30 age-matched healthy controls (HC) were enrolled. First, gray matter volumes (GMV) of the bilateral amygdala were delineated manually in 3D by three blinded experts using the MultiTracer. The whole brain GMV was determined by using voxel-based morphometry. Second, the differences of the whole brain and the bilateral amygdala GMV values between MDD and HC were calculated with t-statistics. The GMV of the whole brain and the amygdala did not differ between HC and MDD patients. Third, MDD characteristics were correlated with amygdala GMV. Within the normal range, the left amygdala GMV was larger in patients with later onset and smaller in cases of prolonged depression. In line with prior reports of depressed patients responding to antidepressant treatment, amygdala GMV was negatively related to illness duration, suggesting volume loss with disease progression. It remains unclear as to whether the association between illness duration and GMV reduced left amygdala volume indicates a neurotoxic effect of prolonged MDD or is rather a negative predictor of chronic depression.


Asunto(s)
Amígdala del Cerebelo/patología , Trastorno Depresivo Mayor/patología , Adulto , Anciano , Amígdala del Cerebelo/diagnóstico por imagen , Trastorno Depresivo Mayor/diagnóstico por imagen , Femenino , Humanos , Interpretación de Imagen Asistida por Computador/métodos , Imagenología Tridimensional/métodos , Imagen por Resonancia Magnética/métodos , Masculino , Persona de Mediana Edad , Neuroimagen/métodos
6.
Brain Behav Immun ; 67: 203-210, 2018 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-28867280

RESUMEN

Major depressive disorder (MDD) is a prevalent disorder with moderate heritability. Both MDD and interpersonal adversity, including childhood maltreatment, have been consistently associated with elevated inflammatory markers. We investigated interaction between exposure to childhood maltreatment and extensive genetic variation within the inflammation pathway (CRP, IL1b, IL-6, IL11, TNF, TNFR1, and TNFR2) in relation to depression diagnosis. The discovery RADIANT sample included 262 cases with recurrent DSM-IV/ICD-10 MDD, and 288 unaffected controls. The replication Münster cohort included 277 cases with DSM-IV MDD, and 316 unaffected controls. We identified twenty-five single nucleotide polymorphisms (SNPs) following multiple testing correction that interacted with childhood maltreatment to predict depression in the discovery cohort. Seven SNPs representing independent signals (rs1818879, rs1041981, rs4149576, rs616645, rs17882988, rs1061622, and rs3093077) were taken forward for replication. Meta-analyses of the two samples presented evidence for interaction with rs1818879 (IL6) (RD=0.059, SE=0.016, p<0.001), with the replication Münster sample approaching statistical significance in analyses restricted to recurrent MDD and controls following correction for multiple testing (q=0.066). The CRP locus (rs3093077) showed a similar level of evidence for interaction in the meta-analysis (RD=0.092, SE=0.029, p=0.002), but less compelling evidence in the replication sample alone (recurrent MDD q=0.198; all MDD q=0.126). Here we present evidence suggestive of interaction with childhood maltreatment for novel loci in IL-6 (rs1818879) and CRP (rs3093077), increasing risk of depression. Replication is needed by independent groups, targeting these specific variants and interaction with childhood maltreatment on depression risk.


Asunto(s)
Trastorno Depresivo Mayor/genética , Trastorno Depresivo Mayor/inmunología , Inflamación/genética , Inflamación/inmunología , Adulto , Adultos Sobrevivientes del Maltrato a los Niños , Proteína C-Reactiva/genética , Estudios de Casos y Controles , Trastorno Depresivo Mayor/complicaciones , Femenino , Interacción Gen-Ambiente , Genotipo , Humanos , Inflamación/complicaciones , Mediadores de Inflamación/metabolismo , Interleucina-6/genética , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Factores de Riesgo
7.
Transl Psychiatry ; 7(9): e1227, 2017 09 05.
Artículo en Inglés | MEDLINE | ID: mdl-28872638

RESUMEN

Representing a phylogenetically old and very basic mechanism of inhibitory neurotransmission, glycine receptors have been implicated in the modulation of behavioral components underlying defensive responding toward threat. As one of the first findings being confirmed by genome-wide association studies for the phenotype of panic disorder and agoraphobia, allelic variation in a gene coding for the glycine receptor beta subunit (GLRB) has recently been associated with increased neural fear network activation and enhanced acoustic startle reflexes. On the basis of two independent healthy control samples, we here aimed to further explore the functional significance of the GLRB genotype (rs7688285) by employing an intermediate phenotype approach. We focused on the phenotype of defensive system reactivity across the levels of brain function, structure, and physiology. Converging evidence across both samples was found for increased neurofunctional activation in the (anterior) insular cortex in GLRB risk allele carriers and altered fear conditioning as a function of genotype. The robustness of GLRB effects is demonstrated by consistent findings across different experimental fear conditioning paradigms and recording sites. Altogether, findings provide translational evidence for glycine neurotransmission as a modulator of the brain's evolutionary old dynamic defensive system and provide further support for a strong, biologically plausible candidate intermediate phenotype of defensive reactivity. As such, glycine-dependent neurotransmission may open up new avenues for mechanistic research on the etiopathogenesis of fear and anxiety disorders.


Asunto(s)
Corteza Cerebral/fisiología , Condicionamiento Clásico/fisiología , Conectoma/métodos , Miedo/fisiología , Receptores de Glicina/genética , Reflejo de Sobresalto/fisiología , Adulto , Corteza Cerebral/diagnóstico por imagen , Alemania , Humanos , Imagen por Resonancia Magnética , Fenotipo
8.
Psychol Med ; 47(12): 2166-2176, 2017 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-28397635

RESUMEN

BACKGROUND: Electroconvulsive therapy (ECT) is one of the most effective treatments for severe depression. However, little is known regarding brain functional processes mediating ECT effects. METHOD: In a non-randomized prospective study, functional magnetic resonance imaging data during the automatic processing of subliminally presented emotional faces were obtained twice, about 6 weeks apart, in patients with major depressive disorder (MDD) before and after treatment with ECT (ECT, n = 24). Additionally, a control sample of MDD patients treated solely with pharmacotherapy (MED, n = 23) and a healthy control sample (HC, n = 22) were obtained. RESULTS: Before therapy, both patient groups equally showed elevated amygdala reactivity to sad faces compared with HC. After treatment, a decrease in amygdala activity to negative stimuli was discerned in both patient samples indicating a normalization of amygdala function, suggesting mechanisms potentially unspecific for ECT. Moreover, a decrease in amygdala activity to sad faces was associated with symptomatic improvements in the ECT sample (r spearman = -0.48, p = 0.044), and by tendency also for the MED sample (r spearman = -0.38, p = 0.098). However, we did not find any significant association between pre-treatment amygdala function to emotional stimuli and individual symptom improvement, neither for the ECT sample, nor for the MED sample. CONCLUSIONS: In sum, the present study provides first results regarding functional changes in emotion processing due to ECT treatment using a longitudinal design, thus validating and extending our knowledge gained from previous treatment studies. A limitation was that ECT patients received concurrent medication treatment.


Asunto(s)
Amígdala del Cerebelo/fisiopatología , Trastorno Depresivo Mayor/fisiopatología , Trastorno Depresivo Mayor/terapia , Terapia Electroconvulsiva/métodos , Imagen por Resonancia Magnética/métodos , Evaluación de Resultado en la Atención de Salud , Adulto , Amígdala del Cerebelo/diagnóstico por imagen , Trastorno Depresivo Mayor/diagnóstico por imagen , Expresión Facial , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos
9.
Artículo en Inglés | MEDLINE | ID: mdl-28259723

RESUMEN

OBJECTIVE: Anxiety disorders are among the most frequent psychiatric disorders. Current treatment guidelines recommend antidepressants, the calcium modulator gabapentin, and benzodiazepines as pharmacological treatments. However, delayed onset of action precludes the use of antidepressants as an acute treatment, while benzodiazepines can be recommended only as an emergency treatment due to their inherent risk of dependence. Therefore, an alternative pharmacological agent with acute efficacy is needed. Preliminary evidence points towards possible anxiolytic properties of the atypical antipsychotic quetiapine. The goals of this study were to test the acute anxiolytic properties of quetiapine in patients suffering from arachnophobia in a challenge paradigm, and to assess the effects of quetiapine on the central nervous fear network. METHODS: In a randomized, double-blind, placebo-controlled proof-of-concept study, n=58 arachnophobic patients underwent an fMRI scan while looking at phobia-related and neutral stimuli. Subjective anxiety was evaluated retrospectively in questionnaires. RESULTS: The functional imaging data revealed that patients showed stronger amygdala activation to phobia-related than to neutral stimuli. However, no effect of quetiapine on fear network activity was detected. Further, on questionnaire measures, quetiapine significantly reduced somatic anxiety symptoms, but had no effect on general psychological anxiety. CONCLUSION: Viewing phobic pictures resulted in a robust amygdala activation in arachnophobic patients. Quetiapine seems to have no influence on activation in anxiety-related brain areas but appears to reduce acute somatic anxiety symptoms in patients with specific phobia. The central nervous correlates of the anxiolytic effects of quetiapine remain to be clarified in future studies.


Asunto(s)
Amígdala del Cerebelo/efectos de los fármacos , Amígdala del Cerebelo/fisiopatología , Ansiolíticos/farmacología , Antipsicóticos/farmacología , Trastornos Fóbicos/tratamiento farmacológico , Trastornos Fóbicos/fisiopatología , Fumarato de Quetiapina/farmacología , Adulto , Amígdala del Cerebelo/diagnóstico por imagen , Ansiolíticos/administración & dosificación , Antipsicóticos/administración & dosificación , Método Doble Ciego , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Trastornos Fóbicos/diagnóstico por imagen , Prueba de Estudio Conceptual , Fumarato de Quetiapina/administración & dosificación , Adulto Joven
10.
Eur Arch Psychiatry Clin Neurosci ; 267(8): 767-779, 2017 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-28337537

RESUMEN

Previous studies suggest an inhibitory top-down control of the amygdala by the prefrontal cortex (PFC). Both brain regions play a role in the modulation of prepulse modification (PPM) of the acoustic startle response by a pre-stimulus. Repetitive transcranial magnetic stimulation (rTMS) can modulate the activity of the PFC and might thus affect PPM. This study tested the effect of inhibitory rTMS on PPM accounting for a genetic variant of the dopamine transporter gene (DAT1). Healthy participants (N = 102) were stimulated with continuous theta burst stimulation (cTBS, an intense form of inhibitory rTMS) or sham treatment over the right PFC. Afterwards, during continuous presentation of a background white noise a louder noise burst was presented either alone (control startle) or preceded by a prepulse. Participants were genotyped for a DAT1 variable number tandem repeat (VNTR) polymorphism. Two succeeding sessions of cTBS over the right PFC (2 × 600 stimuli with a time lag of 15 min) attenuated averaged prepulse inhibition (PPI) in participants with a high resting motor threshold. An attenuation of PPI induced by prepulses with great distances to the pulse (480, 2000 ms) was observed following active cTBS in participants that were homozygous carriers of the 10-repeat-allele of the DAT1 genotype and had a high resting motor threshold. Our results confirm the importance of the prefrontal cortex for the modulation of PPM. The effects were observed in participants with a high resting motor threshold only, probably because they received a higher dose of cTBS. The effects in homozygous carriers of the DAT1 10-repeat allele confirm the relevance of dopamine for PPM. Conducting an exploratory study we decided against the use of a correction for multiple testing.


Asunto(s)
Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/genética , Potenciales Evocados Motores/fisiología , Corteza Prefrontal/fisiología , Inhibición Prepulso/fisiología , Reflejo de Sobresalto/fisiología , Ritmo Teta/fisiología , Estimulación Magnética Transcraneal/métodos , Adulto , Femenino , Genotipo , Humanos , Masculino , Repeticiones de Minisatélite , Polimorfismo Genético , Adulto Joven
11.
Mol Psychiatry ; 22(5): 703-710, 2017 05.
Artículo en Inglés | MEDLINE | ID: mdl-28348383

RESUMEN

Genetic and neuroimaging research has identified neurobiological correlates of obesity. However, evidence for an integrated model of genetic risk and brain structural alterations in the pathophysiology of obesity is still absent. Here we investigated the relationship between polygenic risk for obesity, gray matter structure and body mass index (BMI) by the use of univariate and multivariate analyses in two large, independent cohorts (n=330 and n=347). Higher BMI and higher polygenic risk for obesity were significantly associated with medial prefrontal gray matter decrease, and prefrontal gray matter was further shown to significantly mediate the effect of polygenic risk for obesity on BMI in both samples. Building on this, the successful individualized prediction of BMI by means of multivariate pattern classification algorithms trained on whole-brain imaging data and external validations in the second cohort points to potential clinical applications of this imaging trait marker.


Asunto(s)
Sustancia Gris/anatomía & histología , Sustancia Gris/fisiología , Obesidad/genética , Corteza Prefrontal/anatomía & histología , Corteza Prefrontal/fisiología , Adulto , Algoritmos , Índice de Masa Corporal , Mapeo Encefálico/métodos , Femenino , Predisposición Genética a la Enfermedad , Sustancia Gris/diagnóstico por imagen , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Neuroimagen , Obesidad/etiología , Obesidad/patología , Corteza Prefrontal/diagnóstico por imagen , Factores de Riesgo
12.
Mol Psychiatry ; 22(10): 1431-1439, 2017 10.
Artículo en Inglés | MEDLINE | ID: mdl-28167838

RESUMEN

The molecular genetics of panic disorder (PD) with and without agoraphobia (AG) are still largely unknown and progress is hampered by small sample sizes. We therefore performed a genome-wide association study with a dimensional, PD/AG-related anxiety phenotype based on the Agoraphobia Cognition Questionnaire (ACQ) in a sample of 1370 healthy German volunteers of the CRC TRR58 MEGA study wave 1. A genome-wide significant association was found between ACQ and single non-coding nucleotide variants of the GLRB gene (rs78726293, P=3.3 × 10-8; rs191260602, P=3.9 × 10-8). We followed up on this finding in a larger dimensional ACQ sample (N=2547) and in independent samples with a dichotomous AG phenotype based on the Symptoms Checklist (SCL-90; N=3845) and a case-control sample with the categorical phenotype PD/AG (Ncombined =1012) obtaining highly significant P-values also for GLRB single-nucleotide variants rs17035816 (P=3.8 × 10-4) and rs7688285 (P=7.6 × 10-5). GLRB gene expression was found to be modulated by rs7688285 in brain tissue, as well as cell culture. Analyses of intermediate PD/AG phenotypes demonstrated increased startle reflex and increased fear network, as well as general sensory activation by GLRB risk gene variants rs78726293, rs191260602, rs17035816 and rs7688285. Partial Glrb knockout mice demonstrated an agoraphobic phenotype. In conjunction with the clinical observation that rare coding GLRB gene mutations are associated with the neurological disorder hyperekplexia characterized by a generalized startle reaction and agoraphobic behavior, our data provide evidence that non-coding, although functional GLRB gene polymorphisms may predispose to PD by increasing startle response and agoraphobic cognitions.


Asunto(s)
Agorafobia/genética , Agorafobia/metabolismo , Receptores de Glicina/genética , Adulto , Alelos , Ansiedad/complicaciones , Trastornos de Ansiedad/genética , Encéfalo/metabolismo , Encéfalo/fisiología , Estudios de Casos y Controles , Cognición/fisiología , Miedo/fisiología , Miedo/psicología , Femenino , Frecuencia de los Genes/genética , Predisposición Genética a la Enfermedad/genética , Estudio de Asociación del Genoma Completo , Genotipo , Alemania , Humanos , Masculino , Mutación/genética , Trastorno de Pánico/genética , Receptores de Glicina/metabolismo , Reflejo de Sobresalto/genética
13.
Mol Psychiatry ; 22(7): 1015-1025, 2017 07.
Artículo en Inglés | MEDLINE | ID: mdl-27777418

RESUMEN

Major depressive disorder (MDD) affects around 350 million people worldwide; however, the underlying genetic basis remains largely unknown. In this study, we took into account that MDD is a gene-environment disorder, in which stress is a critical component, and used whole-genome screening of functional variants to investigate the 'missing heritability' in MDD. Genome-wide association studies (GWAS) using single- and multi-locus linear mixed-effect models were performed in a Los Angeles Mexican-American cohort (196 controls, 203 MDD) and in a replication European-ancestry cohort (499 controls, 473 MDD). Our analyses took into consideration the stress levels in the control populations. The Mexican-American controls, comprised primarily of recent immigrants, had high levels of stress due to acculturation issues and the European-ancestry controls with high stress levels were given higher weights in our analysis. We identified 44 common and rare functional variants associated with mild to moderate MDD in the Mexican-American cohort (genome-wide false discovery rate, FDR, <0.05), and their pathway analysis revealed that the three top overrepresented Gene Ontology (GO) processes were innate immune response, glutamate receptor signaling and detection of chemical stimulus in smell sensory perception. Rare variant analysis replicated the association of the PHF21B gene in the ethnically unrelated European-ancestry cohort. The TRPM2 gene, previously implicated in mood disorders, may also be considered replicated by our analyses. Whole-genome sequencing analyses of a subset of the cohorts revealed that European-ancestry individuals have a significantly reduced (50%) number of single nucleotide variants compared with Mexican-American individuals, and for this reason the role of rare variants may vary across populations. PHF21b variants contribute significantly to differences in the levels of expression of this gene in several brain areas, including the hippocampus. Furthermore, using an animal model of stress, we found that Phf21b hippocampal gene expression is significantly decreased in animals resilient to chronic restraint stress when compared with non-chronically stressed animals. Together, our results reveal that including stress level data enables the identification of novel rare functional variants associated with MDD.


Asunto(s)
Trastorno Depresivo Mayor/genética , Adulto , Estudios de Casos y Controles , Femenino , Expresión Génica , Predisposición Genética a la Enfermedad/genética , Estudio de Asociación del Genoma Completo , Humanos , Los Angeles , Masculino , Americanos Mexicanos/genética , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple/genética , Factores de Riesgo , Estrés Psicológico , Población Blanca/genética
14.
Eur Psychiatry ; 40: 33-37, 2017 02.
Artículo en Inglés | MEDLINE | ID: mdl-27837670

RESUMEN

INTRODUCTION: Bipolar Disorder (BD) is a severe psychiatric condition characterized by grey matter (GM) volumes reduction. Neurotrophic factors have been suggested to play a role in the neuroprogressive changes during the illness course. In particular peripheral brain-derived neurotrophic factor (BDNF) has been proposed as a potential biomarker related to disease activity and neuroprogression in BD. The aim of our study was to investigate if serum levels of BDNF are associated with GM volumes in BD patients and healthy controls (HC). METHODS: We studied 36 inpatients affected by a major depressive episode in course of BD type I and 17 HC. Analysis of variance was performed to investigate the effect of diagnosis on GM volumes in the whole brain. Threshold for significance was P<0.05, Family Wise Error (FWE) corrected for multiple comparisons. All the analyses were controlled for the effect of nuisance covariates known to influence GM volumes, such as age, gender and lithium treatment. RESULTS: BD patients showed significantly higher serum BDNF levels compared with HC. Reduced GM volumes in BD patients compared to HC were observed in several brain areas, encompassing the caudate head, superior temporal gyrus, insula, fusiform gyrus, parahippocampal gyrus, and anterior cingulate cortex. The interaction analysis between BDNF levels and diagnosis showed a significant effect in the middle frontal gyrus. HC reported higher BDNF levels associated with higher GM volumes, whereas no association between BDNF and GM volumes was observed in BD. DISCUSSION: Our study seems to suggest that although the production of BDNF is increased in BD possibly to prevent and repair neural damage, its effects could be hampered by underlying neuroinflammatory processes interfering with the neurodevelopmental role of BDNF.


Asunto(s)
Trastorno Bipolar/metabolismo , Factor Neurotrófico Derivado del Encéfalo/sangre , Trastorno Depresivo Mayor/metabolismo , Sustancia Gris/metabolismo , Adulto , Biomarcadores/sangre , Trastorno Bipolar/complicaciones , Trastorno Bipolar/tratamiento farmacológico , Encéfalo/metabolismo , Estudios de Casos y Controles , Corteza Cerebral/efectos de los fármacos , Trastorno Depresivo Mayor/complicaciones , Trastorno Depresivo Mayor/tratamiento farmacológico , Femenino , Giro del Cíngulo/metabolismo , Humanos , Litio/administración & dosificación , Masculino , Persona de Mediana Edad
15.
Genes Brain Behav ; 16(3): 352-360, 2017 03.
Artículo en Inglés | MEDLINE | ID: mdl-27528091

RESUMEN

Tumour necrosis factor alpha (TNFα) has been implicated in the pathophysiology of neurodegenerative and neuropsychiatric disease, with research highlighting a role for TNFα in hippocampal and striatal regulation. TNFα signals are primarily transduced by TNF receptors 1 and 2 (TNFR1 and TNFR2), encoded by TNFRSF1A and TNFRSF1B, which exert opposing effects on cell survival (TNFR1, neurodegenerative; TNFR2, neuroprotective). We therefore sought to explore the respective roles of TNFR1 and TNFR2 in the regulation of hippocampal and striatal morphology in an imaging genetics study. Voxel-based morphometry was used to analyse the associations between TNFRSF1A (rs4149576 and rs4149577) and TNFRSF1B (rs1061624) genotypes and grey matter structure. The final samples comprised a total of 505 subjects (mean age = 33.29, SD = 11.55 years; 285 females and 220 males) for morphometric analyses of rs1061624 and rs4149576, and 493 subjects for rs4149577 (mean age = 33.20, SD = 11.56 years; 281 females and 212 males). Analyses of TNFRSF1A single nucleotide polymorphisms (SNPs) rs4149576 and rs4149577 showed highly significant genotypic associations with striatal volume but not the hippocampus. Specifically, for rs4149576, G homozygotes were associated with reduced caudate nucleus volumes relative to A homozygotes and heterozygotes, whereas for rs4149577, reduced caudate volumes were observed in C homozygotes relative to T homozygotes and heterozygotes. Analysis of the TNFRSF1B SNP rs1061624 yielded a significant association with hippocampal but not with striatal volume, whereby G homozygotes were associated with increased volumes relative to A homozygotes and heterozygotes. Our findings indicate a role for TNFR1 in regulating striatal but not hippocampal morphology, as well as a complementary role for TNFR2 in hippocampal but not in striatal morphology.


Asunto(s)
Cuerpo Estriado/fisiología , Sustancia Gris/fisiología , Hipocampo/fisiología , Receptores Tipo II del Factor de Necrosis Tumoral/genética , Receptores Tipo I de Factores de Necrosis Tumoral/genética , Adulto , Cuerpo Estriado/metabolismo , Femenino , Sustancia Gris/metabolismo , Hipocampo/metabolismo , Humanos , Masculino , Neostriado/metabolismo , Polimorfismo de Nucleótido Simple , Receptores Tipo I de Factores de Necrosis Tumoral/metabolismo , Receptores Tipo II del Factor de Necrosis Tumoral/metabolismo , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/metabolismo
16.
Mol Psychiatry ; 22(6): 900-909, 2017 06.
Artículo en Inglés | MEDLINE | ID: mdl-27137745

RESUMEN

The neuro-anatomical substrates of major depressive disorder (MDD) are still not well understood, despite many neuroimaging studies over the past few decades. Here we present the largest ever worldwide study by the ENIGMA (Enhancing Neuro Imaging Genetics through Meta-Analysis) Major Depressive Disorder Working Group on cortical structural alterations in MDD. Structural T1-weighted brain magnetic resonance imaging (MRI) scans from 2148 MDD patients and 7957 healthy controls were analysed with harmonized protocols at 20 sites around the world. To detect consistent effects of MDD and its modulators on cortical thickness and surface area estimates derived from MRI, statistical effects from sites were meta-analysed separately for adults and adolescents. Adults with MDD had thinner cortical gray matter than controls in the orbitofrontal cortex (OFC), anterior and posterior cingulate, insula and temporal lobes (Cohen's d effect sizes: -0.10 to -0.14). These effects were most pronounced in first episode and adult-onset patients (>21 years). Compared to matched controls, adolescents with MDD had lower total surface area (but no differences in cortical thickness) and regional reductions in frontal regions (medial OFC and superior frontal gyrus) and primary and higher-order visual, somatosensory and motor areas (d: -0.26 to -0.57). The strongest effects were found in recurrent adolescent patients. This highly powered global effort to identify consistent brain abnormalities showed widespread cortical alterations in MDD patients as compared to controls and suggests that MDD may impact brain structure in a highly dynamic way, with different patterns of alterations at different stages of life.


Asunto(s)
Corteza Cerebral/patología , Trastorno Depresivo Mayor/diagnóstico por imagen , Trastorno Depresivo Mayor/patología , Adolescente , Adulto , Encéfalo/patología , Corteza Cerebral/diagnóstico por imagen , Femenino , Lóbulo Frontal/patología , Sustancia Gris/patología , Giro del Cíngulo/patología , Humanos , Imagen por Resonancia Magnética/métodos , Masculino , Neuroimagen/métodos , Neuroimagen/psicología , Corteza Prefrontal/patología , Lóbulo Temporal/patología
17.
Nervenarzt ; 88(9): 1036-1043, 2017 Sep.
Artículo en Alemán | MEDLINE | ID: mdl-27629999

RESUMEN

The use of modern communication and information technology in the health sector, known as eHealth, has the potential to reduce gaps in psychiatric and psychotherapeutic healthcare. In order to successfully implement eHealth it is important to assess the attitude of all stakeholders. The attitude of the patients towards eHealth has been frequently investigated but there is a lack of research on the side of the professionals. The attitude towards eHealth from the perspective of professionals has only rarely been evaluated in German-speaking countries; therefore, we carried out a survey at the German Association for Psychiatry, Psychotherapy and Psychosomatics (DGPPN) congress in 2014 that included 282 psychiatrists, neurologists and psychologists in order to explore their attitudes towards eHealth . Furthermore, the professionals were asked in which therapeutic areas, for which age groups and for which clinical pictures they would expect benefits. In general, the participants expressed a positive attitude towards eHealth . They expected benefits for a multitude of therapeutic areas, particularly for adolescents and adults and especially for the treatment of depression and anxiety disorders; however, they felt only minimally informed about eHealth opportunities indicating a high need for educational and training requirements.


Asunto(s)
Actitud del Personal de Salud , Psiquiatría , Psicoterapia , Telemedicina , Adolescente , Adulto , Anciano , Trastornos de Ansiedad/diagnóstico , Trastornos de Ansiedad/psicología , Trastornos de Ansiedad/terapia , Niño , Trastorno Depresivo/diagnóstico , Trastorno Depresivo/psicología , Trastorno Depresivo/terapia , Trastornos de Alimentación y de la Ingestión de Alimentos/diagnóstico , Trastornos de Alimentación y de la Ingestión de Alimentos/psicología , Trastornos de Alimentación y de la Ingestión de Alimentos/terapia , Femenino , Humanos , Masculino , Persona de Mediana Edad , Satisfacción del Paciente , Proyectos Piloto , Psiquiatría/estadística & datos numéricos , Psicoterapia/estadística & datos numéricos , Trastornos Psicóticos/diagnóstico , Trastornos Psicóticos/psicología , Trastornos Psicóticos/terapia , Trastornos Relacionados con Sustancias/diagnóstico , Trastornos Relacionados con Sustancias/psicología , Trastornos Relacionados con Sustancias/terapia , Encuestas y Cuestionarios , Telemedicina/estadística & datos numéricos , Adulto Joven
19.
Nervenarzt ; 87(9): 1017-29, 2016 Sep.
Artículo en Alemán | MEDLINE | ID: mdl-27531211

RESUMEN

Late-onset depression (LOD) is defined as depression manifesting for the first time in later life. Up to now, there has been no exact definition of the lower age limit for LOD. Psychopathological symptoms of LOD do not fundamentally differ from depression in other phases of life; however, cognitive deficits are typically more pronounced. The LOD is associated with an increased risk of developing dementia. Imaging studies show reduction in gray matter volume and white matter lesions caused by vascular diseases. The occurrence of depression with vascular lesions of the brain is also referred to as "vascular depression". The diagnostic procedure includes a detailed medical history and the observation of psychopathological changes, physical examination, laboratory tests, electroencephalograph (EEG), electrocardiograph (ECG) and magnetic resonance imaging (MRI) of the head and neuropsychological tests to measure cognitive deficits. Psychotherapy is an effective treatment option. Selective serotonin reuptake inhibitors are the first-line pharmacological therapy.


Asunto(s)
Depresión/diagnóstico , Depresión/terapia , Técnicas de Diagnóstico Neurológico , Evaluación Geriátrica/métodos , Enfermedades de Inicio Tardío/diagnóstico , Enfermedades de Inicio Tardío/terapia , Anciano , Anciano de 80 o más Años , Terapia Combinada/métodos , Depresión/psicología , Femenino , Humanos , Enfermedades de Inicio Tardío/psicología , Masculino , Persona de Mediana Edad , Examen Físico/métodos , Psicoterapia/métodos , Inhibidores Selectivos de la Recaptación de Serotonina/uso terapéutico
20.
Transl Psychiatry ; 6: e773, 2016 Apr 05.
Artículo en Inglés | MEDLINE | ID: mdl-27045843

RESUMEN

Epigenetic signatures such as methylation of the monoamine oxidase A (MAOA) gene have been found to be altered in panic disorder (PD). Hypothesizing temporal plasticity of epigenetic processes as a mechanism of successful fear extinction, the present psychotherapy-epigenetic study for we believe the first time investigated MAOA methylation changes during the course of exposure-based cognitive behavioral therapy (CBT) in PD. MAOA methylation was compared between N=28 female Caucasian PD patients (discovery sample) and N=28 age- and sex-matched healthy controls via direct sequencing of sodium bisulfite-treated DNA extracted from blood cells. MAOA methylation was furthermore analyzed at baseline (T0) and after a 6-week CBT (T1) in the discovery sample parallelized by a waiting time in healthy controls, as well as in an independent sample of female PD patients (N=20). Patients exhibited lower MAOA methylation than healthy controls (P<0.001), and baseline PD severity correlated negatively with MAOA methylation (P=0.01). In the discovery sample, MAOA methylation increased up to the level of healthy controls along with CBT response (number of panic attacks; T0-T1: +3.37±2.17%), while non-responders further decreased in methylation (-2.00±1.28%; P=0.001). In the replication sample, increases in MAOA methylation correlated with agoraphobic symptom reduction after CBT (P=0.02-0.03). The present results support previous evidence for MAOA hypomethylation as a PD risk marker and suggest reversibility of MAOA hypomethylation as a potential epigenetic correlate of response to CBT. The emerging notion of epigenetic signatures as a mechanism of action of psychotherapeutic interventions may promote epigenetic patterns as biomarkers of lasting extinction effects.


Asunto(s)
Terapia Cognitivo-Conductual , Metilación de ADN , Epigénesis Genética , Monoaminooxidasa/genética , Trastorno de Pánico/genética , Adulto , Estudios de Casos y Controles , Femenino , Humanos , Trastorno de Pánico/terapia , Análisis de Secuencia de ADN
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