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1.
Am J Med Genet B Neuropsychiatr Genet ; 183(6): 309-330, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32681593

RESUMO

It is imperative to understand the specific and shared etiologies of major depression and cardio-metabolic disease, as both traits are frequently comorbid and each represents a major burden to society. This study examined whether there is a genetic association between major depression and cardio-metabolic traits and if this association is stratified by age at onset for major depression. Polygenic risk scores analysis and linkage disequilibrium score regression was performed to examine whether differences in shared genetic etiology exist between depression case control status (N cases = 40,940, N controls = 67,532), earlier (N = 15,844), and later onset depression (N = 15,800) with body mass index, coronary artery disease, stroke, and type 2 diabetes in 11 data sets from the Psychiatric Genomics Consortium, Generation Scotland, and UK Biobank. All cardio-metabolic polygenic risk scores were associated with depression status. Significant genetic correlations were found between depression and body mass index, coronary artery disease, and type 2 diabetes. Higher polygenic risk for body mass index, coronary artery disease, and type 2 diabetes was associated with both early and later onset depression, while higher polygenic risk for stroke was associated with later onset depression only. Significant genetic correlations were found between body mass index and later onset depression, and between coronary artery disease and both early and late onset depression. The phenotypic associations between major depression and cardio-metabolic traits may partly reflect their overlapping genetic etiology irrespective of the age depression first presents.

2.
Addiction ; 115(3): 482-492, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31833150

RESUMO

BACKGROUND AND AIMS: The use of cannabis has previously been linked to both depression and self-harm; however, the role of genetics in this relationship is unclear. This study aimed to estimate the phenotypic and genetic associations between cannabis use and depression and self-harm. DESIGN: Cross-sectional data collected through UK Biobank were used to test the phenotypic association between cannabis use, depression and self-harm. UK Biobank genetic data were then combined with consortia genome-wide association study summary statistics to further test the genetic relationships between these traits using LD score regression, polygenic risk scoring and Mendelian randomization methods. SETTING: United Kingdom, with additional international consortia data. PARTICIPANTS: A total of 126 291 British adults aged between 40 and 70 years, recruited into UK Biobank. MEASUREMENTS: Phenotypic outcomes were life-time history of cannabis use (including initial and continued cannabis use), depression (including single-episode and recurrent depression) and self-harm. Genome-wide genetic data were used and assessment centre, batch and the first six principal components were included as key covariates when handling genetic data. FINDINGS: In UK Biobank, cannabis use is associated with an increased likelihood of depression [odds ratio (OR) = 1.64, 95% confidence interval (CI) = 1.59-1.70] and self-harm (OR = 2.85, 95% CI = 2.69-3.01). The strength of this phenotypic association is stronger when more severe trait definitions of cannabis use and depression are considered. Using consortia genome-wide summary statistics, significant genetic correlations are seen between cannabis use and depression [rg = 0.289, standard error (SE) = 0.036]. Polygenic risk scores for cannabis use and depression explain a small but significant proportion of variance in cannabis use, depression and self-harm within a UK Biobank target sample. However, two-sample Mendelian randomization analyses were not significant. CONCLUSIONS: Cannabis use appeared to be both phenotypically and genetically associated with depression and self-harm. Limitations in statistical power mean that conclusions could not be made on the direction of causality between these traits.

3.
JMIR Med Inform ; 7(4): e14782, 2019 Dec 17.
Artigo em Inglês | MEDLINE | ID: mdl-31845899

RESUMO

BACKGROUND: Much effort has been put into the use of automated approaches, such as natural language processing (NLP), to mine or extract data from free-text medical records in order to construct comprehensive patient profiles for delivering better health care. Reusing NLP models in new settings, however, remains cumbersome, as it requires validation and retraining on new data iteratively to achieve convergent results. OBJECTIVE: The aim of this work is to minimize the effort involved in reusing NLP models on free-text medical records. METHODS: We formally define and analyze the model adaptation problem in phenotype-mention identification tasks. We identify "duplicate waste" and "imbalance waste," which collectively impede efficient model reuse. We propose a phenotype embedding-based approach to minimize these sources of waste without the need for labelled data from new settings. RESULTS: We conduct experiments on data from a large mental health registry to reuse NLP models in four phenotype-mention identification tasks. The proposed approach can choose the best model for a new task, identifying up to 76% waste (duplicate waste), that is, phenotype mentions without the need for validation and model retraining and with very good performance (93%-97% accuracy). It can also provide guidance for validating and retraining the selected model for novel language patterns in new tasks, saving around 80% waste (imbalance waste), that is, the effort required in "blind" model-adaptation approaches. CONCLUSIONS: Adapting pretrained NLP models for new tasks can be more efficient and effective if the language pattern landscapes of old settings and new settings can be made explicit and comparable. Our experiments show that the phenotype-mention embedding approach is an effective way to model language patterns for phenotype-mention identification tasks and that its use can guide efficient NLP model reuse.

5.
Br J Psychiatry ; 213(5): 645-653, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30232950

RESUMO

BACKGROUND: The medical burden in mood disorders is high; various factors are thought to drive this pattern. Little research has examined the role of childhood maltreatment and its effects on medical morbidity in adulthood among people with unipolar depression and bipolar disorder.AimsThis is the first study to explore the association between childhood maltreatment and medical morbidity in bipolar disorder and in unipolar depression, and examine whether the impact of abuse and neglect are distinct or combined. METHOD: The participants consisted of 354 psychiatrically healthy controls, 248 participants with recurrent unipolar depression and 72 with bipolar disorder. Participants completed the Childhood Trauma Questionnaire and received a validated medical history interview. RESULTS: Any type of childhood maltreatment, child abuse and child neglect were significantly associated with the medical burden in bipolar disorder, but not unipolar depression or for controls. These associations worked in a dose-response fashion where participants with bipolar disorder with a history of two or more types of childhood maltreatment had the highest odds of having a medical illness relative to those without such history or those who reported one form. No such significant dose-response patterns were detected for participants with unipolar depression or controls. CONCLUSIONS: These findings suggest that childhood maltreatment may play a stronger role in the development of medical illnesses in individuals with bipolar disorder relative to those with unipolar depression. Individuals who had been maltreated with a mood disorder, especially bipolar disorder may benefit most from prevention and intervention efforts surrounding physical health.Declaration of interestNone.


Assuntos
Sobreviventes Adultos de Maus-Tratos Infantis/psicologia , Transtorno Bipolar/epidemiologia , Maus-Tratos Infantis/psicologia , Transtorno Depressivo/epidemiologia , Adulto , Sobreviventes Adultos de Maus-Tratos Infantis/estatística & dados numéricos , Estudos de Casos e Controles , Criança , Comorbidade , Feminino , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Escalas de Graduação Psiquiátrica , Fatores de Risco , Inquéritos e Questionários , Reino Unido/epidemiologia
6.
PLoS One ; 13(9): e0203896, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30240446

RESUMO

There are currently no reliable approaches for correctly identifying which patients with major depressive disorder (MDD) will respond well to antidepressant therapy. However, recent genetic advances suggest that Polygenic Risk Scores (PRS) could allow MDD patients to be stratified for antidepressant response. We used PRS for MDD and PRS for neuroticism as putative predictors of antidepressant response within three treatment cohorts: The Genome-based Therapeutic Drugs for Depression (GENDEP) cohort, and 2 sub-cohorts from the Pharmacogenomics Research Network Antidepressant Medication Pharmacogenomics Study PRGN-AMPS (total patient number = 760). Results across cohorts were combined via meta-analysis within a random effects model. Overall, PRS for MDD and neuroticism did not significantly predict antidepressant response but there was a consistent direction of effect, whereby greater genetic loading for both MDD (best MDD result, p < 5*10-5 MDD-PRS at 4 weeks, ß = -0.019, S.E = 0.008, p = 0.01) and neuroticism (best neuroticism result, p < 0.1 neuroticism-PRS at 8 weeks, ß = -0.017, S.E = 0.008, p = 0.03) were associated with less favourable response. We conclude that the PRS approach may offer some promise for treatment stratification in MDD and should now be assessed within larger clinical cohorts.


Assuntos
Antidepressivos/uso terapêutico , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Maior/genética , Neuroticismo/efeitos dos fármacos , Estudos de Coortes , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Masculino , Herança Multifatorial , Variantes Farmacogenômicos , Polimorfismo de Nucleotídeo Único , Análise de Componente Principal , Fatores de Risco , Inibidores de Captação de Serotonina/uso terapêutico
7.
Sci Rep ; 8(1): 5530, 2018 04 03.
Artigo em Inglês | MEDLINE | ID: mdl-29615645

RESUMO

Individuals with depression differ substantially in their response to treatment with antidepressants. Specific predictors explain only a small proportion of these differences. To meaningfully predict who will respond to which antidepressant, it may be necessary to combine multiple biomarkers and clinical variables. Using statistical learning on common genetic variants and clinical information in a training sample of 280 individuals randomly allocated to 12-week treatment with antidepressants escitalopram or nortriptyline, we derived models to predict remission with each antidepressant drug. We tested the reproducibility of each prediction in a validation set of 150 participants not used in model derivation. An elastic net logistic model based on eleven genetic and six clinical variables predicted remission with escitalopram in the validation dataset with area under the curve 0.77 (95%CI; 0.66-0.88; p = 0.004), explaining approximately 30% of variance in who achieves remission. A model derived from 20 genetic variables predicted remission with nortriptyline in the validation dataset with an area under the curve 0.77 (95%CI; 0.65-0.90; p < 0.001), explaining approximately 36% of variance in who achieves remission. The predictive models were antidepressant drug-specific. Validated drug-specific predictions suggest that a relatively small number of genetic and clinical variables can help select treatment between escitalopram and nortriptyline.


Assuntos
Biomarcadores/análise , Citalopram/uso terapêutico , Transtorno Depressivo Maior/tratamento farmacológico , Nortriptilina/uso terapêutico , Adulto , Antidepressivos de Segunda Geração/uso terapêutico , Antidepressivos Tricíclicos/uso terapêutico , Transtorno Depressivo Maior/genética , Transtorno Depressivo Maior/patologia , Feminino , Humanos , Masculino , Resultado do Tratamento
8.
Hum Mol Genet ; 26(R2): R160-R165, 2017 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-28977440

RESUMO

There has been substantial progress in psychiatric genetics in recent years, through collaborative efforts to build large samples sizes for case/control analyses for a number of psychiatric disorders. The identification of replicated trait-associated genomic loci represents a large stride forward in a field where little is known about the biological processes involved in disorder. As researchers build on this early foundation, they are beginning to advance the field towards more fine-grained approaches that interrogate the many sources of heterogeneity within psychiatric genetics that can obscure the identification of genotypic influences on disorder. In this review, we provide a brief overview, across a range of psychiatric diagnoses, of recent approaches that have been employed to dissect heterogeneity to give a flavour of the current direction of the field. We group these into three main categories; tackling the heterogeneity in phenotype that is found within the diagnostic categories used within psychiatry, the many different forms of genetic variation that might influence psychiatric traits and then finally, the heterogeneity that is seen across individuals of different ancestries.


Assuntos
Heterogeneidade Genética , Transtornos Mentais/genética , Estudos de Casos e Controles , Predisposição Genética para Doença/genética , Genética Populacional , Genótipo , Humanos , Transtornos Mentais/diagnóstico , Fenótipo , Psiquiatria/métodos
9.
Hum Brain Mapp ; 38(8): 3757-3770, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28480992

RESUMO

Despite over 400 peer-reviewed structural MRI publications documenting neuroanatomic abnormalities in bipolar disorder and schizophrenia, the confounding effects of head motion and the regional specificity of these defects are unclear. Using a large cohort of individuals scanned on the same research dedicated MRI with broadly similar protocols, we observe reduced cortical thickness indices in both illnesses, though less pronounced in bipolar disorder. While schizophrenia (n = 226) was associated with wide-spread surface area reductions, bipolar disorder (n = 227) and healthy comparison subjects (n = 370) did not differ. We replicate earlier reports that head motion (estimated from time-series data) influences surface area and cortical thickness measurements and demonstrate that motion influences a portion, but not all, of the observed between-group structural differences. Although the effect sizes for these differences were small to medium, when global indices were covaried during vertex-level analyses, between-group effects became nonsignificant. This analysis raises doubts about the regional specificity of structural brain changes, possible in contrast to functional changes, in affective and psychotic illnesses as measured with current imaging technology. Given that both schizophrenia and bipolar disorder showed cortical thickness reductions, but only schizophrenia showed surface area changes, and assuming these measures are influenced by at least partially unique sets of biological factors, then our results could indicate some degree of specificity between bipolar disorder and schizophrenia. Hum Brain Mapp 38:3757-3770, 2017. © 2017 Wiley Periodicals, Inc.


Assuntos
Transtorno Bipolar/diagnóstico por imagem , Encéfalo/diagnóstico por imagem , Imagem por Ressonância Magnética , Movimento (Física) , Esquizofrenia/diagnóstico por imagem , Adulto , Estudos de Coortes , Diagnóstico Diferencial , Feminino , Cabeça , Humanos , Processamento de Imagem Assistida por Computador , Masculino , Modelos Biológicos , Tamanho do Órgão , Escalas de Graduação Psiquiátrica
10.
J Neurosci ; 37(18): 4735-4743, 2017 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-28385874

RESUMO

The accurate estimation of age using methylation data has proved a useful and heritable biomarker, with acceleration in epigenetic age predicting a number of age-related phenotypes. Measures of white matter integrity in the brain are also heritable and highly sensitive to both normal and pathological aging processes across adulthood. We consider the phenotypic and genetic interrelationships between epigenetic age acceleration and white matter integrity in humans. Our goal was to investigate processes that underlie interindividual variability in age-related changes in the brain. Using blood taken from a Mexican-American extended pedigree sample (n = 628; age = 23.28-93.11 years), epigenetic age was estimated using the method developed by Horvath (2013). For n = 376 individuals, diffusion tensor imaging scans were also available. The interrelationship between epigenetic age acceleration and global white matter integrity was investigated with variance decomposition methods. To test for neuroanatomical specificity, 16 specific tracts were additionally considered. We observed negative phenotypic correlations between epigenetic age acceleration and global white matter tract integrity (ρpheno = -0.119, p = 0.028), with evidence of shared genetic (ρgene = -0.463, p = 0.013) but not environmental influences. Negative phenotypic and genetic correlations with age acceleration were also seen for a number of specific white matter tracts, along with additional negative phenotypic correlations between granulocyte abundance and white matter integrity. These findings (i.e., increased acceleration in epigenetic age in peripheral blood correlates with reduced white matter integrity in the brain and shares common genetic influences) provide a window into the neurobiology of aging processes within the brain and a potential biomarker of normal and pathological brain aging.SIGNIFICANCE STATEMENT Epigenetic measures can be used to predict age with a high degree of accuracy and so capture acceleration in biological age, relative to chronological age. The white matter tracts within the brain are also highly sensitive to aging processes. We show that increased biological aging (measured using epigenetic data from blood samples) is correlated with reduced integrity of white matter tracts within the human brain (measured using diffusion tensor imaging) with data from a large sample of Mexican-American families. Given the family design of the sample, we are also able to demonstrate that epigenetic aging and white matter tract integrity also share common genetic influences. Therefore, epigenetic age may be a potential, and accessible, biomarker of brain aging.


Assuntos
Envelhecimento/genética , Imagem de Tensor de Difusão/métodos , Epigênese Genética/genética , Substância Branca/anatomia & histologia , Substância Branca/fisiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Simulação por Computador , Conectoma/métodos , Feminino , Humanos , Interpretação de Imagem Assistida por Computador/métodos , Masculino , Pessoa de Meia-Idade , Modelos Genéticos , Adulto Jovem
11.
Am J Med Genet B Neuropsychiatr Genet ; 174(4): 427-434, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28394502

RESUMO

Antidepressant-induced hippocampal neurogenesis (AHN) is hypothesized to contribute to increases in hippocampal volume among major depressive disorder patients after long-term treatment. Furthermore, rodent studies suggest AHN may be the cellular mechanism mediating the therapeutic benefits of antidepressants. Here, we perform the first investigation of genome-wide expression changes associated with AHN in human cells. We identify gene expression networks significantly activated during AHN, and we perform gene set analyses to probe the molecular relationship between AHN, hippocampal volume, and antidepressant response. The latter were achieved using genome-wide association summary data collected from 30,717 individuals as part of the ENIGMA Consortium (genetic predictors of hippocampal volume dataset), and data collected from 1,222 major depressed patients as part of the NEWMEDS Project (genetic predictors of response to antidepressants dataset). Our results showed that the selective serotonin reuptake inhibitor, escitalopram evoked AHN in human cells; dose-dependently increasing the differentiation of cells into neuroblasts, as well as increasing gliogenesis. Activated genome-wide expression networks relate to axon and microtubule formation, and ribosomal biogenesis. Gene set analysis revealed that gene expression changes associated with AHN were nominally enriched for genes predictive of hippocampal volume, but not for genes predictive of therapeutic response.


Assuntos
Citalopram/farmacologia , Transtorno Depressivo Maior/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Genoma Humano , Estudo de Associação Genômica Ampla , Hipocampo/metabolismo , Neurogênese/genética , Antidepressivos de Segunda Geração/farmacologia , Células Cultivadas , Transtorno Depressivo Maior/tratamento farmacológico , Redes Reguladoras de Genes/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Humanos , Neurogênese/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo
12.
Addiction ; 112(1): 113-123, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27517884

RESUMO

BACKGROUND AND AIMS: While the prevalence of major depression is elevated among cannabis users, the role of genetics in this pattern of comorbidity is not clear. This study aimed to estimate the heritability of cannabis use and major depression, quantify the genetic overlap between these two traits and localize regions of the genome that segregate in families with cannabis use and major depression. DESIGN: Family-based univariate and bivariate genetic analysis. SETTING: San Antonio, Texas, USA. PARTICIPANTS: Genetics of Brain Structure and Function study (GOBS) participants: 1284 Mexican Americans from 75 large multi-generation families and an additional 57 genetically unrelated spouses. MEASUREMENTS: Phenotypes of life-time history of cannabis use and major depression, measured using the semistructured MINI-Plus interview. Genotypes measured using ~1 M single nucleotide polymorphisms (SNPs) on Illumina BeadChips. A subselection of these SNPs were used to build multi-point identity-by-descent matrices for linkage analysis. FINDINGS: Both cannabis use [h2  = 0.614, P = 1.00 × 10-6 , standard error (SE) = 0.151] and major depression (h2  = 0.349, P = 1.06 × 10-5 , SE = 0.100) are heritable traits, and there is significant genetic correlation between the two (ρg  = 0.424, P = 0.0364, SE = 0.195). Genome-wide linkage scans identify a significant univariate linkage peak for major depression on chromosome 22 [logarithm of the odds (LOD) = 3.144 at 2 centimorgans (cM)], with a suggestive peak for cannabis use on chromosome 21 (LOD = 2.123 at 37 cM). A significant pleiotropic linkage peak influencing both cannabis use and major depression was identified on chromosome 11 using a bivariate model (LOD = 3.229 at 112 cM). Follow-up of this pleiotropic signal identified a SNP 20 kb upstream of NCAM1 (rs7932341) that shows significant bivariate association (P = 3.10 × 10-5 ). However, this SNP is rare (seven minor allele carriers) and does not drive the linkage signal observed. CONCLUSIONS: There appears to be a significant genetic overlap between cannabis use and major depression among Mexican Americans, a pleiotropy that appears to be localized to a region on chromosome 11q23 that has been linked previously to these phenotypes.


Assuntos
Transtorno Depressivo Maior/epidemiologia , Predisposição Genética para Doença/epidemiologia , Abuso de Maconha/epidemiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Comorbidade , Transtorno Depressivo Maior/genética , Grupos Étnicos/psicologia , Grupos Étnicos/estatística & dados numéricos , Feminino , Humanos , Masculino , Abuso de Maconha/genética , Pessoa de Meia-Idade , Texas/epidemiologia , Adulto Jovem
13.
Cereb Cortex ; 27(12): 5539-5546, 2017 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-27744290

RESUMO

Head movements are typically viewed as a nuisance to functional magnetic resonance imaging (fMRI) analysis, and are particularly problematic for resting state fMRI. However, there is growing evidence that head motion is a behavioral trait with neural and genetic underpinnings. Using data from a large randomly ascertained extended pedigree sample of Mexican Americans (n = 689), we modeled the genetic structure of head motion during resting state fMRI and its relation to 48 other demographic and behavioral phenotypes. A replication analysis was performed using data from the Human Connectome Project, which uses an extended twin design (n = 864). In both samples, head motion was significantly heritable (h2 = 0.313 and 0.427, respectively), and phenotypically correlated with numerous traits. The most strongly replicated relationship was between head motion and body mass index, which showed evidence of shared genetic influences in both data sets. These results highlight the need to view head motion in fMRI as a complex neurobehavioral trait correlated with a number of other demographic and behavioral phenotypes. Given this, when examining individual differences in functional connectivity, the confounding of head motion with other traits of interest needs to be taken into consideration alongside the critical important of addressing head motion artifacts.


Assuntos
Índice de Massa Corporal , Movimentos da Cabeça , Imagem por Ressonância Magnética , Fenótipo , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Conectoma , Feminino , Estudos de Associação Genética , Humanos , Padrões de Herança , Masculino , Americanos Mexicanos/genética , Pessoa de Meia-Idade , Descanso , Fatores Sexuais , Adulto Jovem
14.
Eur Neuropsychopharmacol ; 26(1): 105-112, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26621261

RESUMO

The mechanisms by which antidepressants have their effects are not clear and the reasons for variability in treatment outcomes are also unknown. However, there is evidence from candidate gene research that indicates gene expression changes may be involved in antidepressant action. In this study, we examined antidepressant-induced alterations in gene expression on a transcriptome-wide scale, exploring associations with treatment response. Blood samples were taken from a subset of depressed patients from the GENDEP study (n=136) before and after eight weeks of treatment with either escitalopram or nortriptyline. Transcriptomic data were obtained from these samples using Illumina HumanHT-12 v4 Expression BeadChip microarrays. When analysing individual genes, we observed that changes in the expression of two genes (MMP28 and KXD1) were associated with better response to nortriptyline. Considering connectivity between genes, we identified modules of genes that were highly coexpressed. In the whole sample, changes in one of the ten identified coexpression modules showed significant correlation with treatment response (cor=0.27, p=0.0029). Using transcriptomic approaches, we have identified gene expression correlates of the therapeutic effects of antidepressants, highlighting possible molecular pathways involved in efficacious antidepressant treatment.


Assuntos
Antidepressivos/uso terapêutico , Citalopram/uso terapêutico , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Maior/metabolismo , Nortriptilina/uso terapêutico , Transcriptoma/efeitos dos fármacos , Proteínas de Transporte/metabolismo , Estudos de Coortes , Transtorno Depressivo Maior/genética , Europa (Continente) , Grupo com Ancestrais do Continente Europeu , Expressão Gênica/efeitos dos fármacos , Humanos , Metaloproteinases da Matriz Secretadas/metabolismo , Análise em Microsséries , Resultado do Tratamento
15.
Psychopharmacology (Berl) ; 232(14): 2609-17, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25761838

RESUMO

RATIONALE: Cytochrome P450 enzymes are important in the metabolism of antidepressants. The highly polymorphic nature of these enzymes has been linked to variability in antidepressant metabolism rates, leading to hope regarding the use of P450 genotyping to guide treatment. However, evidence that P450 genotypic differences underlie the variation in treatment outcomes is inconclusive. OBJECTIVES: We explored the links between both P450 genotype and serum concentrations of antidepressant with antidepressant side effects, using data from the Genome-Based Therapeutic Drugs for Depression Project (GENDEP), which is a large (n = 868), pharmacogenetic study of depressed individuals treated with escitalopram or nortriptyline. METHODS: Patients were genotyped for the enzymes CYP2C19 and CYP2D6, and serum concentrations of both antidepressant and primary metabolite were measured after 8 weeks of treatment. Side effects were assessed weekly. We investigated associations between P450 genotypes, serum concentrations of antidepressants and side effects, as well as the relationship between P450 genotype and study discontinuation. RESULTS: P450 genotype did not predict total side effect burden (nortriptyline: n = 251, p = 0.5638, ß = -0.133, standard error (SE) = 0.229; escitalopram: n = 340, p = 0.9627, ß = -0.004, SE = 0.085), study discontinuation (nortriptyline n = 284, hazard ratio (HR) = 1.300, p = 0.174; escitalopram n = 376, HR = 0.870, p = 0.118) or specific side effects. Serum concentrations of antidepressant were only related to a minority of the specific side effects measured: dry mouth, dizziness and diarrhoea. CONCLUSIONS: In this sample where antidepressant dosage is titrated using clinical judgement, P450 genotypes do not explain differences between patients in side effects with antidepressants. Serum drug concentrations appear to only explain variability in the occurrence of a minority of specific side effects.


Assuntos
Antidepressivos/efeitos adversos , Sistema Enzimático do Citocromo P-450/metabolismo , Adulto , Antidepressivos/farmacocinética , Antidepressivos/uso terapêutico , Antidepressivos de Segunda Geração/efeitos adversos , Antidepressivos de Segunda Geração/farmacocinética , Antidepressivos de Segunda Geração/uso terapêutico , Antidepressivos Tricíclicos/efeitos adversos , Antidepressivos Tricíclicos/farmacocinética , Antidepressivos Tricíclicos/uso terapêutico , Citalopram/efeitos adversos , Citalopram/uso terapêutico , Estudos de Coortes , Citocromo P-450 CYP2C19/genética , Citocromo P-450 CYP2D6/genética , Depressão/tratamento farmacológico , Depressão/genética , Depressão/psicologia , Feminino , Genótipo , Humanos , Masculino , Nortriptilina/efeitos adversos , Nortriptilina/farmacocinética , Nortriptilina/uso terapêutico , Resultado do Tratamento
16.
J Psychopharmacol ; 28(2): 142-50, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24414086

RESUMO

BACKGROUND: The unwanted side effects associated with antidepressants are key determinants of treatment adherence in depression; propensity to experience these adverse drug reactions (ADRs) may be influenced by genetic variation. However, previous work attempting to ascertain the genetic variants involved has had limited success, in part due to the range of ADRs reported with antidepressants. METHOD: ADRs reported with antidepressant treatment were categorised using their likely pharmacological basis; adrenergic, cholinergic, serotonergic and histaminergic. To identify genetic predictors of susceptibility to each group of ADRs, a candidate gene analysis was performed with data from 431 depressed patients (from a total sample size of 811 patients) enrolled in the Genome-Based Therapeutic Drugs for Depression (GENDEP) project, who were randomly allocated to receive treatment with escitalopram or nortriptyline. Data from 474 patients treated with citalopram or reboxetine in the GenPod project (total sample of 601 patients) were used for replication of significant findings. RESULTS: We found no significant predictors of presumed adrenergic, cholinergic and histaminergic ADRs. Putative serotonergic ADRs were significantly associated with variation in the gene encoding the serotonin 2C receptor (HTR2C, rs6644093, odds ratio (OR)=1.72, 95% confidence interval (CI)=1.31-2.25, p=7.43×10(-5)) in GENDEP. However, this finding was not replicated in GenPod. CONCLUSIONS: The association between serotonergic side effects and variation in the HTR2C gene in the GENDEP sample supports the hypothesis that serotonin receptor-mediated mechanisms underlie these adverse reactions, however this finding was not replicated in GenPod.


Assuntos
Antidepressivos/efeitos adversos , Depressão/tratamento farmacológico , Receptor 5-HT2C de Serotonina/genética , Adulto , Idoso , Depressão/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Receptor 5-HT2B de Serotonina/genética
17.
Depress Anxiety ; 31(4): 326-34, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24338983

RESUMO

BACKGROUND: We test the hypothesis that the functional Val66Met polymorphism of BDNF interacts with recent life events to produce onset of new depressive episodes. We also explore the possibility that the Met allele of this polymorphism interacts with childhood maltreatment to increase the risk of chronic depression. METHODS: In a risk-enriched combined sample of unrelated women, childhood maltreatment and current life events were measured with the Childhood Experience of Care and Abuse, and Life Events and Difficulties Schedule interviews. Chronic episodes of depression (12 months or longer) during adulthood and onset of a major depressive episode during a 12-month follow-up were established with the Schedules for Clinical Assessment in Neuropsychiatry interview. RESULTS: Met alleles of BDNF moderated the relationship between recent life events and adult onsets of depression in a significant gene-environment interaction (interaction risk difference 0.216, 95% CI 0.090-0.342; P =.0008). BDNF did not significantly influence the effect of childhood maltreatment on chronic depression in the present sample. CONCLUSIONS: The Met allele of BDNF increases the risk of a new depressive episode following a severe life event. The BDNF and the serotonin transporter gene length polymorphism (5-HTTLPR) and BDNF may contribute to depression through distinct mechanisms involving interactions with childhood and adulthood adversity respectively, which may, in combination, be responsible for a substantial proportion of depression burden in the general population.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/genética , Maus-Tratos Infantis/psicologia , Transtorno Depressivo/genética , Interação Gene-Ambiente , Acontecimentos que Mudam a Vida , Polimorfismo Genético/genética , Adulto , Criança , Transtorno Depressivo/psicologia , Inglaterra , Feminino , Humanos , Metionina , Pessoa de Meia-Idade , Fatores de Risco , Estresse Psicológico/genética , Estresse Psicológico/psicologia , Valina , Adulto Jovem
18.
J Psychopharmacol ; 28(2): 133-41, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24257813

RESUMO

AIMS: Antidepressant response varies between patients, possibly due to differences in the rate cytochrome P450 enzymes metabolise antidepressants into inactive compounds. Drug metabolism rates are influenced by common variants in the genes encoding these enzymes. However, it remains unclear whether treatment outcomes can be predicted by either CYP450 genotype or antidepressant serum concentration. METHODS: In GENDEP (a pharmacogenetic study of depressed individuals treated with either escitalopram or nortriptyline), serum concentrations of antidepressants and their primary metabolite were measured after eight weeks treatment and variants in CYP2D6 and CYP2C19 were genotyped. RESULTS: Amongst patients taking escitalopram (n=223), the genotype CYP2C19 was significantly associated with escitalopram serum concentrations and desmethylescitalopram:escitalopram ratio. For those taking nortriptyline (n=161), the CYP2D6 genotype was significantly associated with nortriptyline and 10-hydroxynortriptyline serum concentrations and 10-hydroxynortriptyline:nortrip-tyline ratio. CYP450 genotypes conferring greater enzyme activity were linked to lower drug serum concentrations and higher metabolite:drug ratios. Nonetheless, no significant association was found between either CYP450 genotype or antidepressant serum concentration and treatment response. CONCLUSIONS: While there is a significant relationship between the CYP450 genotype and serum concentrations of escitalopram and nortriptyline, the genotypes are not predictive of differences in treatment response for either drug. Furthermore, differences in antidepressant serum concentrations are not associated with variability in treatment response.


Assuntos
Antidepressivos/uso terapêutico , Hidrocarboneto de Aril Hidroxilases/genética , Citocromo P-450 CYP2D6/genética , Citalopram/sangue , Citalopram/uso terapêutico , Citocromo P-450 CYP2C19 , Genótipo , Humanos , Nortriptilina/análogos & derivados , Nortriptilina/sangue , Nortriptilina/uso terapêutico
19.
Curr Top Behav Neurosci ; 14: 81-99, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-22918611

RESUMO

Since the publication of the working draft of the human genome just over a decade ago, there have been dramatic advances in our understanding of the role genetics play in both normal human functioning as well as in disease. The identification of genes, which influence an individual's susceptibility to depression, is not only an intriguing scientific endeavour in its own right, but further, if a gene can be confidently implicated in depression, then this could shed light on the aetiological processes involved in the disease. Moreover, a genetic association with depression may identify targets for consideration in the development of novel treatments for the illness. This chapter will summarise the current research into the genetic basis of depression. A number of genes of interest have been highlighted, although a genetic variant, that is unequivocally associated with increased risk for the disease, is yet to be identified. However, technologies and methodologies are evolving rapidly, and genetic approaches have helped shape how we conceptualise depression as an illness.


Assuntos
Depressão/genética , Predisposição Genética para Doença/genética , Animais , Humanos
20.
Sci Rep ; 2: 593, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22919460

RESUMO

Humans bargaining over money tend to reject unfair offers, whilst chimpanzees bargaining over primary rewards of food do not show this same motivation to reject. Whether such reciprocal fairness represents a predominantly human motivation has generated considerable recent interest. We induced either moderate or severe thirst in humans using intravenous saline, and examined responses to unfairness in an Ultimatum Game with water. We ask if humans also reject unfair offers for primary rewards. Despite the induction of even severe thirst, our subjects rejected unfair offers. Further, our data provide tentative evidence that this fairness motivation was traded-off against the value of the primary reward to the individual, a trade-off determined by the subjective value of water rather than by an objective physiological metric of value. Our data demonstrate humans care about fairness during bargaining with primary rewards, but that subjective self-interest may limit this fairness motivation.


Assuntos
Comportamento/fisiologia , Jogos Experimentais , Recompensa , Tomada de Decisões , Humanos
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