RESUMEN
BACKGROUND: Personality traits may predict antidepressant discontinuation and response. However, previous studies were rather small, only explored a few personality traits and did not include adverse drug effects nor the interdependency between antidepressant discontinuation patterns and response. METHODS: GENDEP included 589 patients with unipolar moderate-severe depression treated with escitalopram or nortriptyline for 12 weeks. Seven personality dimensions were measured using the self-reported 240-item Temperament and Character Inventory-Revised (TCI-R). We applied Cox proportional models to study discontinuation patterns, logistic and linear regression to investigate response and remission after 8 and 12 weeks, and mixed-effects linear models regarding time-varying treatment response and adverse drug reactions. RESULTS: Low harm avoidance, low cooperativeness, high self-transcendence and high novelty seeking were associated with higher risks for antidepressant discontinuation, independent of depressed mood, adverse drug reactions, drug, sex and age. Regression analyses showed that higher novelty seeking and cooperativeness scores were associated with a greater likelihood of response and remission after 8 and 12 weeks, respectively, but we found no correlations with response in the mixed-effects models. Only high harm avoidance was associated with more self-reported adverse effects. CONCLUSIONS: This study, representing the largest investigation between several personality traits and response to two different antidepressants, suggests that correlations between personality traits and antidepressant treatment response may be confounded by differential rates of discontinuation. Future trials on personality in the treatment of depression need to consider this interdependency and study whether interventions aiming at improving compliance for some personality types may improve response to antidepressants.
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Trastorno Depresivo Mayor , Temperamento , Humanos , Escitalopram , Nortriptilina/efectos adversos , Trastorno Depresivo Mayor/tratamiento farmacológico , Carácter , Antidepresivos/efectos adversos , Inventario de PersonalidadRESUMEN
Humans differ substantially in how strongly they respond to similar experiences. Theory suggests that such individual differences in susceptibility to environmental influences have a genetic basis. The present study investigated the genetic architecture of Environmental Sensitivity (ES) by estimating its heritability, exploring the presence of multiple heritable components and its genetic overlap with common personality traits. ES was measured with the Highly Sensitive Child (HSC) questionnaire and heritability estimates were obtained using classic twin design methodology in a sample of 2868 adolescent twins. Results indicate that the heritability of sensitivity was 0.47, and that the genetic influences underlying sensitivity to negative experiences are relatively distinct from sensitivity to more positive aspects of the environment, supporting a multi-dimensional genetic model of ES. The correlation between sensitivity, neuroticism and extraversion was largely explained by shared genetic influences, with differences between these traits mainly attributed to unique environmental influences operating on each trait.
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Modelos Genéticos , Gemelos , Adolescente , Niño , Humanos , Neuroticismo , Fenotipo , Encuestas y Cuestionarios , Gemelos/genéticaRESUMEN
BACKGROUND: Whilst genetic and environmental risk factors for schizophrenia (SCZ) and major depressive disorder (MDD) have been established, it is unclear whether exposure to environmental risk factors is genetically confounded by passive, evocative or active gene-environment correlation (rGE). STUDY OBJECTIVE: This study aims to investigate: (a) whether the genetic risk for SCZ/MDD in children is correlated with established environmental and psychosocial risk factors in two British community samples, the 1958 National Child Development Study (NCDS) and the Millennium Cohort Study (MCS), (b) whether these associations vary between both psychopathologies, and (c) whether findings differ across the two cohorts which were born 42 years apart. METHODS: Polygenic risk scores (PRS) from existing large genome-wide associations studies (GWAS) were applied to test the correlation between the child genetic risk for SCZ/MDD and known environmental risk factors. In addition, parental and child genetic data from MCS were used to distinguish between passive and evocative rGE. RESULTS: The child polygenic risk for SCZ and MDD was correlated with single parenthood in MCS. Moreover, the lack of father's involvement in child care was associated with the genetic risk for SCZ in NCDS. However, we also found associations between several indicators of low socioeconomic status and heightened genetic risk for MDD in children in both cohorts. Further, the genetic risk for MDD was associated with parental lack of interest in the child's education in NCDS as well as more maternal smoking and less maternal alcohol consumption during childhood in MCS. According to sensitivity analyses in MCS (controlling for parental genotype), more than half of our significant correlations reflected passive rGE. CONCLUSIONS: Findings suggest that several established environmental and psychosocial risk factors for SCZ and MDD are at least partially associated with children's genetic risk for these psychiatric disorders.
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Trastorno Depresivo Mayor , Esquizofrenia , Estudios de Cohortes , Depresión , Trastorno Depresivo Mayor/etiología , Trastorno Depresivo Mayor/genética , Interacción Gen-Ambiente , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Humanos , Herencia Multifactorial , Factores de Riesgo , Esquizofrenia/epidemiología , Esquizofrenia/genéticaRESUMEN
Empirical studies suggest that psychiatric disorders result from a complex interplay between genetic and environmental factors. Most evidence for such gene-environment interaction (GxE) is based on single candidate gene studies conducted from a Diathesis-Stress perspective. Recognizing the short-comings of candidate gene studies, GxE research has begun to focus on genome-wide and polygenic approaches as well as drawing on different theoretical concepts underlying GxE, such as Differential Susceptibility. After reviewing evidence from candidate GxE studies and presenting alternative theoretical frameworks underpinning GxE research, more recent approaches and findings from whole genome approaches are presented. Finally, we suggest how future GxE studies may unpick the complex interplay between genes and environments in psychiatric disorders.
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Interacción Gen-Ambiente , Predisposición Genética a la Enfermedad/genética , Trastornos Mentales/genética , Estrés Psicológico/genética , Estrés Psicológico/psicología , Trastorno de Personalidad Antisocial/genética , Trastorno por Déficit de Atención con Hiperactividad/genética , Catecol O-Metiltransferasa/genética , Depresión/genética , Ambiente , Humanos , Monoaminooxidasa/genética , Receptores de Dopamina D4/genética , Esquizofrenia/genética , Proteínas de Transporte de Serotonina en la Membrana Plasmática/genéticaRESUMEN
Differential DNA methylation of the hypothalamic-pituitary-adrenal axis related gene FKBP5 has recently been shown to be associated with varying response to environmental influences and may play a role in how well people respond to psychological treatments. Participants (n = 111) received exposure-based cognitive behavioural therapy (CBT) for agoraphobia with or without panic disorder, or specific phobias. Percentage DNA methylation levels were measured for the promoter region and intron 7 of FKBP5. The association between percentage reduction in clinical severity and change in DNA methylation was tested using linear mixed models. The effect of genotype (rs1360780) was tested by the inclusion of an interaction term. The association between change in DNA methylation and FKBP5 expression was examined. Change in percentage DNA methylation at one CpG site of intron 7 was associated with percentage reduction in severity (ß = -4.26, p = 3.90 × 10-4 ), where a decrease in DNA methylation was associated with greater response to therapy. An interaction was detected between rs1360780 and changes in DNA methylation in the promoter region of FKBP5 on treatment outcome (p = .045) but did not survive correction for multiple testing. Changes in DNA methylation were not associated with FKBP5 expression. Decreasing DNA methylation at one CpG site of intron 7 of FKBP5 was strongly associated with decreasing anxiety severity following exposure-based CBT. In addition, there was suggestive evidence that allele-specific methylation at the promoter region may also be associated with treatment response. The results of this study add to the growing literature demonstrating the role of biological processes such as DNA methylation in response to environmental influences.
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Agorafobia/genética , Terapia Implosiva/métodos , Proteínas de Unión a Tacrolimus/genética , Adulto , Anciano , Agorafobia/terapia , Terapia Cognitivo-Conductual/métodos , Metilación de ADN/genética , Epigénesis Genética/genética , Femenino , Genotipo , Humanos , Sistema Hipotálamo-Hipofisario/metabolismo , Intrones/genética , Masculino , Persona de Mediana Edad , Sistema Hipófiso-Suprarrenal/metabolismo , Polimorfismo de Nucleótido Simple/genética , Regiones Promotoras Genéticas/genética , Proteínas de Unión a Tacrolimus/metabolismo , Resultado del TratamientoRESUMEN
BACKGROUND: Several delivery formats of cognitive behaviour therapy (CBT) for child anxiety have been proposed, however, there is little consensus on the optimal delivery format. The primary goal of this study was to investigate the impact of the child's primary anxiety diagnosis on changes in clinical severity (of the primary problem) during individual CBT, group CBT and guided parent-led CBT. The secondary goal was to investigate the impact of the child's primary anxiety diagnosis on rates of remission for the three treatment formats. METHODS: A sample of 1,253 children (5-12 years; Mage = 9.3, SD = 1.7) was pooled from CBT trials carried out at 10 sites. Children had a primary diagnosis of generalised anxiety disorder (GAD), social anxiety disorder (SoAD), specific phobia (SP) or separation anxiety disorder (SAD). Children and parents completed a semistructured clinical interview to assess the presence and severity of DSM-IV psychiatric disorders at preintervention, postintervention and follow-up. Linear mixture modelling was used to evaluate the primary research question and logistic modelling was used to investigate the secondary research question. RESULTS: In children with primary GAD, SAD or SoAD, there were no significant differences between delivery formats. However, children with primary SP showed significantly larger reductions in clinical severity following individual CBT compared to group CBT and guided parent-led CBT. The results were mirrored in the analysis of remission responses with the exception that individual CBT was no longer superior to group CBT for children with a primary SP. The difference between individual and group was not significant when follow-up data were examined separately. CONCLUSIONS: Data show there may be greater clinical benefit by allocating children with a primary SP to individual CBT, although future research on cost-effectiveness is needed to determine whether the additional clinical benefits justify the additional resources required.
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Trastornos de Ansiedad/terapia , Terapia Cognitivo-Conductual/métodos , Evaluación de Procesos y Resultados en Atención de Salud , Padres , Psicoterapia de Grupo/métodos , Ansiedad de Separación/terapia , Niño , Preescolar , Femenino , Humanos , Masculino , Fobia Social/terapia , Trastornos Fóbicos/terapia , Inducción de Remisión , Índice de Severidad de la EnfermedadRESUMEN
While environmental adversity has been shown to increase risk for psychopathology, individuals differ in their sensitivity to these effects. Both genes and childhood experiences are thought to influence sensitivity to the environment, and these factors may operate synergistically such that the effects of childhood experiences on later sensitivity are greater in individuals who are more genetically sensitive. In line with this hypothesis, several recent studies have reported a significant three-way interaction (Gene × Environment × Environment) between two candidate genes and childhood and adult environment on adult psychopathology. We aimed to replicate and extend these findings in a large, prospective multiwave longitudinal study using a polygenic score of environmental sensitivity and objectively measured childhood and adult material environmental quality. We found evidence for both Environment × Environment and Gene × Environment × Environment effects on psychological distress. Children with a poor-quality material environment were more sensitive to the negative effects of a poor environment as adults, reporting significantly higher psychological distress scores. These effects were further moderated by a polygenic score of environmental sensitivity. Genetically sensitive children were more vulnerable to adversity as adults, if they had experienced a poor childhood environment but were significantly less vulnerable if their childhood environment was positive. These findings are in line with the differential susceptibility hypothesis and suggest that a life course approach is necessary to elucidate the role of Gene × Environment in the development of mental illnesses.
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Interacción Gen-Ambiente , Trastornos Mentales/genética , Medio Social , Estrés Psicológico/genética , Adolescente , Adulto , Niño , Empleo , Femenino , Vivienda , Humanos , Estudios Longitudinales , Masculino , Trastornos Mentales/psicología , Persona de Mediana Edad , Herencia Multifactorial , Estudios Prospectivos , Factores de Riesgo , Clase Social , Estrés Psicológico/psicología , Reino Unido , Adulto JovenRESUMEN
Emotion recognition is disrupted in many mental health disorders, which may reflect shared genetic aetiology between this trait and these disorders. We explored genetic influences on emotion recognition and the relationship between these influences and mental health phenotypes. Eight-year-old participants (n = 4,097) from the Avon Longitudinal Study of Parents and Children (ALSPAC) completed the Diagnostic Analysis of Non-Verbal Accuracy (DANVA) faces test. Genome-wide genotype data was available from the Illumina HumanHap550 Quad microarray. Genome-wide association studies were performed to assess associations with recognition of individual emotions and emotion in general. Exploratory polygenic risk scoring was performed using published genomic data for schizophrenia, bipolar disorder, depression, autism spectrum disorder, anorexia, and anxiety disorders. No individual genetic variants were identified at conventional levels of significance in any analysis although several loci were associated at a level suggestive of significance. SNP-chip heritability analyses did not identify a heritable component of variance for any phenotype. Polygenic scores were not associated with any phenotype. The effect sizes of variants influencing emotion recognition are likely to be small. Previous studies of emotion identification have yielded non-zero estimates of SNP-heritability. This discrepancy is likely due to differences in the measurement and analysis of the phenotype.
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Emociones/fisiología , Reconocimiento Facial/fisiología , Marcadores Genéticos , Estudio de Asociación del Genoma Completo , Herencia Multifactorial , Trastornos del Neurodesarrollo/genética , Polimorfismo de Nucleótido Simple , Niño , Expresión Facial , Femenino , Estudios de Seguimiento , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Estudios Longitudinales , Masculino , Fenotipo , Pronóstico , Estudios ProspectivosRESUMEN
Extinction learning is an important mechanism in the successful psychological treatment of anxiety. Individual differences in response and relapse following Cognitive Behavior Therapy may in part be explained by variability in the ease with which fears are extinguished or the vulnerability of these fears to re-emerge. Given the role of the endocannabinoid system in fear extinction, this study investigates whether genetic variation in the endocannabinoid system explains individual differences in response to CBT. Children (N = 1,309) with a primary anxiety disorder diagnosis were recruited. We investigated the relationship between variation in the CNR1, CNR2, and FAAH genes and change in primary anxiety disorder severity between pre- and post-treatment and during the follow-up period in the full sample and a subset with fear-based anxiety disorder diagnoses. Change in symptom severity during active treatment was nominally associated (P < 0.05) with two SNPs. During the follow-up period, five SNPs were nominally associated with a poorer treatment response (rs806365 [CNR1]; rs2501431 [CNR2]; rs2070956 [CNR2]; rs7769940 [CNR1]; rs2209172 [FAAH]) and one with a more favorable response (rs6928813 [CNR1]). Within the fear-based subset, the effect of rs806365 survived multiple testing corrections (P < 0.0016). We found very limited evidence for an association between variants in endocannabinoid system genes and treatment response once multiple testing corrections were applied. Larger, more homogenous cohorts are needed to allow the identification of variants of small but statistically significant effect and to estimate effect sizes for these variants with greater precision in order to determine their potential clinical utility. © 2016 The Authors. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics Published by Wiley Periodicals, Inc.
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Trastornos de Ansiedad/genética , Endocannabinoides/genética , Adolescente , Amidohidrolasas/genética , Amidohidrolasas/metabolismo , Ansiedad/genética , Niño , Terapia Cognitivo-Conductual/métodos , Endocannabinoides/metabolismo , Miedo/psicología , Femenino , Variación Genética/genética , Humanos , Masculino , Polimorfismo de Nucleótido Simple/genética , Receptor Cannabinoide CB1/genética , Receptor Cannabinoide CB1/metabolismo , Receptor Cannabinoide CB2/genética , Receptor Cannabinoide CB2/metabolismo , Resultado del TratamientoRESUMEN
BACKGROUND: We previously reported an association between 5HTTLPR genotype and outcome following cognitive-behavioural therapy (CBT) in child anxiety (Cohort 1). Children homozygous for the low-expression short-allele showed more positive outcomes. Other similar studies have produced mixed results, with most reporting no association between genotype and CBT outcome. AIMS: To replicate the association between 5HTTLPR and CBT outcome in child anxiety from the Genes for Treatment study (GxT Cohort 2, n = 829). METHOD: Logistic and linear mixed effects models were used to examine the relationship between 5HTTLPR and CBT outcomes. Mega-analyses using both cohorts were performed. RESULTS: There was no significant effect of 5HTTLPR on CBT outcomes in Cohort 2. Mega-analyses identified a significant association between 5HTTLPR and remission from all anxiety disorders at follow-up (odds ratio 0.45, P = 0.014), but not primary anxiety disorder outcomes. CONCLUSIONS: The association between 5HTTLPR genotype and CBT outcome did not replicate. Short-allele homozygotes showed more positive treatment outcomes, but with small, non-significant effects. Future studies would benefit from utilising whole genome approaches and large, homogenous samples.
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Trastornos de Ansiedad/genética , Trastornos de Ansiedad/terapia , Terapia Cognitivo-Conductual , Interacción Gen-Ambiente , Proteínas de Transporte de Serotonina en la Membrana Plasmática/genética , Adolescente , Alelos , Niño , Preescolar , Femenino , Genotipo , Humanos , Masculino , Escalas de Valoración Psiquiátrica , Inducción de Remisión , Resultado del TratamientoRESUMEN
BACKGROUND: Anxiety disorders are common, and cognitive-behavioural therapy (CBT) is a first-line treatment. Candidate gene studies have suggested a genetic basis to treatment response, but findings have been inconsistent. AIMS: To perform the first genome-wide association study (GWAS) of psychological treatment response in children with anxiety disorders (n = 980). METHOD: Presence and severity of anxiety was assessed using semi-structured interview at baseline, on completion of treatment (post-treatment), and 3 to 12 months after treatment completion (follow-up). DNA was genotyped using the Illumina Human Core Exome-12v1.0 array. Linear mixed models were used to test associations between genetic variants and response (change in symptom severity) immediately post-treatment and at 6-month follow-up. RESULTS: No variants passed a genome-wide significance threshold (P = 5 × 10(-8)) in either analysis. Four variants met criteria for suggestive significance (P<5 × 10(-6)) in association with response post-treatment, and three variants in the 6-month follow-up analysis. CONCLUSIONS: This is the first genome-wide therapygenetic study. It suggests no common variants of very high effect underlie response to CBT. Future investigations should maximise power to detect single-variant and polygenic effects by using larger, more homogeneous cohorts.
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Trastornos de Ansiedad/genética , Terapia Cognitivo-Conductual , Estudio de Asociación del Genoma Completo , Adolescente , Trastornos de Ansiedad/terapia , Niño , Preescolar , Femenino , Genotipo , Humanos , Masculino , Polimorfismo de Nucleótido Simple/genética , Resultado del TratamientoRESUMEN
BACKGROUND: The differential susceptibly hypothesis suggests that certain genetic variants moderate the effects of both negative and positive environments on mental health and may therefore be important predictors of response to psychological treatments. Nevertheless, the identification of such variants has so far been limited to preselected candidate genes. In this study we extended the differential susceptibility hypothesis from a candidate gene to a genome-wide approach to test whether a polygenic score of environmental sensitivity predicted response to cognitive behavioural therapy (CBT) in children with anxiety disorders. METHODS: We identified variants associated with environmental sensitivity using a novel method in which within-pair variability in emotional problems in 1,026 monozygotic twin pairs was examined as a function of the pairs' genotype. We created a polygenic score of environmental sensitivity based on the whole-genome findings and tested the score as a moderator of parenting on emotional problems in 1,406 children and response to individual, group and brief parent-led CBT in 973 children with anxiety disorders. RESULTS: The polygenic score significantly moderated the effects of parenting on emotional problems and the effects of treatment. Individuals with a high score responded significantly better to individual CBT than group CBT or brief parent-led CBT (remission rates: 70.9, 55.5 and 41.6%, respectively). CONCLUSIONS: Pending successful replication, our results should be considered exploratory. Nevertheless, if replicated, they suggest that individuals with the greatest environmental sensitivity may be more likely to develop emotional problems in adverse environments but also benefit more from the most intensive types of treatment.
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Trastornos de Ansiedad/genética , Trastornos de Ansiedad/terapia , Terapia Cognitivo-Conductual/métodos , Estudio de Asociación del Genoma Completo , Herencia Multifactorial , Responsabilidad Parental , Niño , Femenino , Predisposición Genética a la Enfermedad , Humanos , Modelos Lineales , Modelos Logísticos , Masculino , Salud MentalRESUMEN
BACKGROUND: Hypothalamic-pituitary-adrenal (HPA) axis functioning has been implicated in the development of stress-related psychiatric diagnoses and response to adverse life experiences. This study aimed to investigate the association between genetic and epigenetics in HPA axis and response to cognitive behavior therapy (CBT). METHODS: Children with anxiety disorders were recruited into the Genes for Treatment project (GxT, N = 1,152). Polymorphisms of FKBP5 and GR were analyzed for association with response to CBT. Percentage DNA methylation at the FKBP5 and GR promoter regions was measured before and after CBT in a subset (n = 98). Linear mixed effect models were used to investigate the relationship between genotype, DNA methylation, and change in primary anxiety disorder severity (treatment response). RESULTS: Treatment response was not associated with FKBP5 and GR polymorphisms, or pretreatment percentage DNA methylation. However, change in FKBP5 DNA methylation was nominally significantly associated with treatment response. Participants who demonstrated the greatest reduction in severity decreased in percentage DNA methylation during treatment, whereas those with little/no reduction in severity increased in percentage DNA methylation. This effect was driven by those with one or more FKBP5 risk alleles, with no association seen in those with no FKBP5 risk alleles. No significant association was found between GR methylation and response. CONCLUSIONS: Allele-specific change in FKBP5 methylation was associated with treatment response. This is the largest study to date investigating the role of HPA axis related genes in response to a psychological therapy. Furthermore, this is the first study to demonstrate that DNA methylation changes may be associated with response to psychological therapies in a genotype-dependent manner.
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Trastornos de Ansiedad/genética , Terapia Cognitivo-Conductual , Sistema Hipotálamo-Hipofisario/fisiopatología , Sistema Hipófiso-Suprarrenal/fisiopatología , Receptores de Glucocorticoides/genética , Proteínas de Unión a Tacrolimus/genética , Adolescente , Alelos , Trastornos de Ansiedad/terapia , Niño , Preescolar , Metilación de ADN/genética , Epigénesis Genética/genética , Epigenómica , Femenino , Humanos , Masculino , Polimorfismo de Nucleótido Simple , Resultado del TratamientoRESUMEN
BACKGROUND: Traditional diagnoses of major depressive disorder (MDD) suggested that the presence or absence of stress prior to onset results in either 'reactive' or 'endogenous' subtypes of the disorder, respectively. Several lines of research suggest that the biological underpinnings of 'reactive' or 'endogenous' subtypes may also differ, resulting in differential response to treatment. We investigated this hypothesis by comparing the gene-expression profiles of three animal models of 'reactive' and 'endogenous' depression. We then translated these findings to clinical samples using a human post-mortem mRNA study. METHODS: Affymetrix mouse whole-genome oligonucleotide arrays were used to measure gene expression from hippocampal tissues of 144 mice from the Genome-based Therapeutic Drugs for Depression (GENDEP) project. The study used four inbred mouse strains and two depressogenic 'stress' protocols (maternal separation and Unpredictable Chronic Mild Stress) to model 'reactive' depression. Stress-related mRNA differences in mouse were compared with a parallel mRNA study using Flinders Sensitive and Resistant rat lines as a model of 'endogenous' depression. Convergent genes differentially expressed across the animal studies were used to inform candidate gene selection in a human mRNA post-mortem case control study from the Stanley Brain Consortium. RESULTS: In the mouse 'reactive' model, the expression of 350 genes changed in response to early stresses and 370 in response to late stresses. A minimal genetic overlap (less than 8.8%) was detected in response to both stress protocols, but 30% of these genes (21) were also differentially regulated in the 'endogenous' rat study. This overlap is significantly greater than expected by chance. The VAMP-2 gene, differentially expressed across the rodent studies, was also significantly altered in the human study after correcting for multiple testing. CONCLUSIONS: Our results suggest that 'endogenous' and 'reactive' subtypes of depression are associated with largely distinct changes in gene-expression. However, they also suggest that the molecular signature of 'reactive' depression caused by early stressors differs considerably from that of 'reactive' depression caused by late stressors. A small set of genes was consistently dysregulated across each paradigm and in post-mortem brain tissue of depressed patients suggesting a final common pathway to the disorder. These genes included the VAMP-2 gene, which has previously been associated with Axis-I disorders including MDD, bipolar depression, schizophrenia and with antidepressant treatment response. We also discuss the implications of our findings for disease classification, personalized medicine and case-control studies of MDD.
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Trastornos de Adaptación/genética , Trastorno Depresivo Mayor/genética , Trastorno Depresivo/genética , Modelos Animales de Enfermedad , Regulación de la Expresión Génica , Estrés Psicológico/genética , Animales , Antidepresivos/uso terapéutico , Encéfalo/patología , Estudios de Casos y Controles , Depresión/diagnóstico , Depresión/genética , Trastorno Depresivo/diagnóstico , Trastorno Depresivo Mayor/clasificación , Femenino , Expresión Génica , Hipocampo , Humanos , Masculino , Privación Materna , Ratones , Análisis de Secuencia por Matrices de Oligonucleótidos , ARN Mensajero/análisis , ARN Mensajero/genética , Ratas , Proteína 2 de Membrana Asociada a Vesículas/genéticaRESUMEN
BACKGROUND: Although genetic and environmental factors are involved in the aetiology of bipolar disorder [BD], studies focused on their interplay are lacking. The current investigation examines interactions and correlations between polygenic risk scores [PRS] for BD and major depressive disorder [MDD] with stressful life events [SLEs] in liability for BD. METHODS: This study used data from 1715 participants (862 bipolar cases and 853 controls) taken from UK and Canadian samples. The List of Threatening Experiences Questionnaire recorded SLEs that occurred 6 months before interview for controls and 6 months prior to the first (Canadian sample) and worst (UK sample) depressive and manic episodes for bipolar cases. PRS-BD and PRS-MDD were calculated from the Psychiatric Genomics Consortium. RESULTS: For the worst depressive episode, the PRS-MDD was significantly correlated with total number of SLEs (ß = 0.13, 95 % CI:0.04-0.22, p = 0.003) and dependent SLEs (ß = 0.09, 95 % CI:0.02-0.16, p = 0.007). After correction for multiple testing nominally significant correlations were detected for PRS-BD with total number of SLEs (ß = 0.11, 95 % CI:0.02-0.20, p = 0.015) and dependent SLEs (ß = 0.08, 95 % CI:0.01-0.15, p = 0.019). Among bipolar cases, these associations were slightly stronger but were only of nominal significance for total number of SLEs (PRS-MDD: ß = 0.19, 95 % CI:0.04-0.35, p = 0.015; PRS-BD: ß = 0.16, 95 % CI:0.01-0.32, p = 0.042) and dependent SLEs (PRS-MDD: ß = 0.14, 95 % CI:0.03-0.26, p = 0.015; PRS-BD: ß = 0.12, 95 % CI:0.004-0.24, p = 0.043). No other significant gene-environment correlations or interactions were found. LIMITATIONS: Use of a larger sample size would be beneficial. CONCLUSIONS: The relationship between SLEs and genetic risk for mood disorders may be best explained through correlations rather than interactions.
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Trastorno Bipolar , Trastorno Depresivo Mayor , Humanos , Trastorno Bipolar/genética , Trastorno Bipolar/psicología , Trastornos del Humor , Trastorno Depresivo Mayor/genética , Trastorno Depresivo Mayor/psicología , Canadá , Herencia Multifactorial , Puntuación de Riesgo GenéticoRESUMEN
In this study, we present a pharmacoproteomic investigation of response to antidepressants two inbred strains. Our aim was to uncover molecular mechanisms underlying antidepressant action and identify new biomarkers to determine therapeutic response to two antidepressants with proven efficacy in the treatment of depression but divergent mechanisms of action. Mice were treated with the pro-noradrenergic drug nortriptyline, the pro-serotonergic drug escitalopram or saline. Quantitative proteomic analyses were undertaken on hippocampal tissue from a study design that used two inbred mouse strains, two depressogenic protocols and a control condition, (maternal separation, chronic mild stress, control), two antidepressant drugs and two dosing protocols. The proteomic analysis was aimed at the identification of specific drug-response markers. Complementary approaches, 2DE and isobaric tandem mass tagging (TMT), were applied to the selected experimental groups. To investigate the relationship between proteomic profiles, depressogenic protocols and drug response, 2DE and TMT data sets were analysed using multivariate methods. The results highlighted significant strain- and stress-related differences across both 2DE and TMT data sets and identified the three gene products involved in serotonergic (PXBD5, YHWAB, SLC25A4) and one in noradrenergic antidepressant action (PXBD6).
Asunto(s)
Antidepresivos/farmacología , Hipocampo/efectos de los fármacos , Proteoma/efectos de los fármacos , Estrés Psicológico/tratamiento farmacológico , Proteínas 14-3-3/genética , Proteínas 14-3-3/metabolismo , Translocador 1 del Nucleótido Adenina/genética , Translocador 1 del Nucleótido Adenina/metabolismo , Animales , Citalopram/farmacología , Electroforesis en Gel Bidimensional , Femenino , Hipocampo/química , Hipocampo/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos , Análisis Multivariante , Nortriptilina/farmacología , Peroxirredoxinas/genética , Peroxirredoxinas/metabolismo , Análisis de Componente Principal , Proteoma/análisis , Proteómica , Reproducibilidad de los Resultados , Espectrometría de Masas en Tándem , DesteteRESUMEN
RATIONALE: Monoaminergic imbalances play a role in the pathogenesis of depression and most common antidepressant drugs act on monoamine neurotransmitters. However, the lag time between restoring neurochemical balance and symptom improvement suggests that the response to drugs involves complex biological events downstream of primary targets that have not yet been fully characterized. Here, we report a mouse mRNA expression study to evaluate the effect of escitalopram (a serotonergic antidepressant) and nortriptyline (a noradrenergic antidepressant) on genes that are involved in the pathogenesis of depression and to assess the similarities and differences between two drugs on gene expression levels. METHODS: Genome-wide RNA expression data from the hippocampal tissues of four inbred mouse strains (129S1/SvlmJ, C57LB/6J, DBA/2J and FVB/NJ) were treated with varying doses of either nortriptyline (NRI) or escitalopram (SSRI) and subjected to two different depressogenic protocols. Following robust multichip average normalization, we applied the nonparametric RankProd approach to identify differentially expressed genes in response to drugs across the four strains. Pathway analysis was subsequently carried out on top-ranking genes to gain further biological insights. RESULTS: A total of 371 genes were significantly differentially expressed in response to nortriptyline, whereas 383 were altered by escitalopram. Genes involved in the pathways of integrin signalling (Fnlb, Mapk1, Mapk8), synaptic transmission (Cacnb1, Dnajc5, Kcnma1, Slc1a2) or Huntington disease (Crebbp, Dlg4, Ncor1) were altered by both nortriptyline and escitalopram. Several biological processes and pathways were identified, which could explain the divergence between the molecular mechanisms of nortriptyline and escitalopram. CONCLUSION: From a large-scale animal study, we obtain gene sets comprised of commonly and differentially expressed genes in response to different antidepressant drug treatments. The results may help to characterize the response to antidepressant treatment, shed further light on the neurobiology of depressive disorders and inform future animal and human studies. Finally, the top-ranking pathways from Ingenuity provide further evidence for the hippocampal neurogenesis hypothesis of major depressive disorders.
Asunto(s)
Antidepresivos/farmacología , Citalopram/farmacología , Depresión/tratamiento farmacológico , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Nortriptilina/farmacología , ARN Mensajero/metabolismo , Animales , Antidepresivos/uso terapéutico , Citalopram/uso terapéutico , Depresión/patología , Modelos Animales de Enfermedad , Hipocampo/patología , Ratones , Neurogénesis/efectos de los fármacos , Nortriptilina/uso terapéuticoRESUMEN
BACKGROUND: Cognitive biases have long been hypothesized to influence the development and maintenance of symptoms of internalizing problems. Anxiety sensitivity represents one such bias and refers to sensitivity to the physical and emotional symptoms of anxiety and the belief that these are harmful. Twin studies indicate a role for both environmental and genetic influences on anxiety sensitivity. However, little work has been done specifying environments or genes involved in this phenotype. In light of this, we looked at the association between stressful life events, the serotonin transporter gene polymorphism (5HTTLPR), and anxiety sensitivity in a longitudinal sample of adolescents. METHODS: Stressful life events and anxiety sensitivity were measured in over 1,500 individuals at three time points (mean ages 15, 17, and 20 years). 5HTTLPR was genotyped in 1,109 participants. RESULTS: There was consistent evidence for an association between stressful life events and both anxiety sensitivity and change in anxiety sensitivity over time. Although the effect of independent stressful life events was relatively short lived, dependent stressful life events were associated with anxiety sensitivity over time. There was no evidence for a main effect of 5HTTLPR on anxiety sensitivity. 5HTTLPR genotype did not moderate the effect of stressful life events on anxiety sensitivity. CONCLUSIONS: The current study extends previous work by showing that stressful life events, independent of the individual, explained change in cognitions associated with anxiety and depression. This effect does not, however, appear to be moderated by genotype.
Asunto(s)
Ansiedad/genética , Interacción Gen-Ambiente , Acontecimientos que Cambian la Vida , Proteínas de Transporte de Serotonina en la Membrana Plasmática/genética , Proteínas de Transporte de Serotonina en la Membrana Plasmática/metabolismo , Adolescente , Adulto , Ansiedad/metabolismo , Ansiedad/psicología , Niño , Femenino , Genotipo , Humanos , Estudios Longitudinales , Masculino , Polimorfismo Genético , Encuestas y Cuestionarios , Factores de Tiempo , Adulto JovenRESUMEN
Response to antidepressants is interindividually variable. It has been suggested that this variability is a direct consequence of etiological heterogeneity. Therefore, the same genes, environments, and gene-environment interactions implicated in different etiological pathways to depression may also predict response to treatment. This article reviews the evidence relevant to this hypothesis by first outlining the roles of genes, environments, and gene-environment interplay in the etiology of depression, and then considering the same factors in treatment response. Environmental exposures, such as childhood maltreatment, are potent predictors of both depression and treatment response. Although alone genetic factors have failed to consistently predict either phenotype, several polymorphisms have been shown to moderate the effects of environmental adversity on the development of depression and treatment response. These findings suggest that the dissection of etiological pathways to depression may provide the key to understanding and predicting response to antidepressants.
Asunto(s)
Antidepresivos/uso terapéutico , Trastorno Depresivo Mayor/tratamiento farmacológico , Interacción Gen-Ambiente , Trastorno Depresivo Mayor/genética , Trastorno Depresivo Mayor/psicología , Humanos , Acontecimientos que Cambian la Vida , Factores de Riesgo , Estrés Psicológico/psicología , Resultado del TratamientoRESUMEN
Genome-wide studies in major depression have identified few replicated associations, potentially due to heterogeneity within the disorder. Several studies have suggested that age at onset (AAO) can distinguish sub-types of depression with specific heritable components. This paper investigates the role of AAO in the genetic susceptibility for depression using genome-wide association data on 2,746 cases and 1,594 screened controls from the RADIANT studies, with replication performed in 1,471 cases and 1,403 controls from two Munich studies. Three methods were used to analyze AAO: First a time-to-event analysis with controls censored, secondly comparing controls to case-subsets defined using AAO cut-offs, and lastly analyzing AAO as a quantitative trait. In the time-to-event analysis three SNPs reached suggestive significance (P < 5E-06), overlapping with the original case-control analysis of this study. In a case-control analysis using AAO thresholds, SNPs in 10 genomic regions showed suggestive association though again none reached genome-wide significance. Lastly, case-only analysis of AAO as a quantitative trait resulted in 5 SNPs reaching suggestive significance. Sex specific analysis was performed as a secondary analysis, yielding one SNP reaching genome-wide significance in early-onset males. No SNPs achieved significance in the replication study after correction for multiple testing. Analysis of AAO as a quantitative trait did suggest that, across all SNPs, common genetic variants explained a large proportion of the variance (51%, P = 0.04). This study provides the first focussed analysis of the genetic contribution to AAO in depression, and establishes a statistical framework that can be applied to a quantitative trait underlying any disorder.