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1.
Eur Neuropsychopharmacol ; 44: 105-120, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33483252

RESUMO

There is a recurring debate on the role of the serotonin transporter gene linked polymorphic region (5-HTTLPR) in the moderation of response to cognitive behavioral therapy (CBT) in anxiety disorders. Results, however, are still inconclusive. We here aim to perform a meta-analysis on the role of 5-HTTLPR in the moderation of CBT outcome in anxiety disorders. We investigated both categorical (symptom reduction of at least 50%) and dimensional outcomes from baseline to post-treatment and follow-up. Original data were obtained from ten independent samples (including three unpublished samples) with a total of 2,195 patients with primary anxiety disorder. No significant effects of 5-HTTLPR genotype on categorical or dimensional outcomes at post and follow-up were detected. We conclude that current evidence does not support the hypothesis of 5-HTTLPR as a moderator of treatment outcome for CBT in anxiety disorders. Future research should address whether other factors such as long-term changes or epigenetic processes may explain further variance in these complex gene-environment interactions and molecular-genetic pathways that may confer behavioral change following psychotherapy.

2.
Epigenetics ; : 1-18, 2020 Dec 29.
Artigo em Inglês | MEDLINE | ID: mdl-33371772

RESUMO

Accumulating evidence suggests that individuals exposed to victimization at key developmental stages may have different epigenetic fingerprints compared to those exposed to no/minimal stressful events, however results are inconclusive. This study aimed to strengthen causal inference regarding the impact of adolescent victimization on the epigenome by controlling for genetic variation, age, gender, and shared environmental exposures. We conducted longitudinal epigenome-wide association analyses (EWAS) on DNA methylation (DNAm) profiles of 118 monozygotic (MZ) twin pairs from the Environmental Risk study with and without severe adolescent victimization generated using buccal DNA collected at ages 5, 10 and 18, and the Illumina EPIC array. Additionally, we performed cross-sectional EWAS on age-18 blood and buccal DNA from the same individuals to elucidate tissue-specific signatures of severe adolescent victimization. Our analyses identified 20 suggestive differentially methylated positions (DMPs) (P < 5e-05), with altered DNAm trajectories between ages 10-18 associated with severe adolescent victimization (∆Beta range = -5.5%-5.3%). Age-18 cross-sectional analyses revealed 72 blood (∆Beta range = -2.2%-3.4%) and 42 buccal (∆Beta range = -3.6%-4.6%) suggestive severe adolescent victimization-associated DMPs, with some evidence of convergent signals between these two tissue types. Downstream regional analysis identified significant differentially methylated regions (DMRs) in LGR6 and ANK3 (Sidák P =  5e-09 and 4.07e-06), and one upstream of CCL27 (Sidák P = 2.80e-06) in age-18 blood and buccal EWAS, respectively. Our study represents the first longitudinal MZ twin analysis of DNAm and severe adolescent victimization, providing initial evidence for altered DNA methylomic signatures in individuals exposed to adolescent victimization.

3.
Nat Commun ; 10(1): 5339, 2019 11 25.
Artigo em Inglês | MEDLINE | ID: mdl-31767861

RESUMO

Female somatic X-chromosome inactivation (XCI) balances the X-linked transcriptional dosages between the sexes. Skewed XCI toward one parental X has been observed in several complex human traits, but the extent to which genetics and environment influence skewed XCI is largely unexplored. To address this, we quantify XCI-skew in multiple tissues and immune cell types in a twin cohort. Within an individual, XCI-skew differs between blood, fat and skin tissue, but is shared across immune cell types. XCI skew increases with age in blood, but not other tissues, and is associated with smoking. XCI-skew is increased in twins with Rheumatoid Arthritis compared to unaffected identical co-twins. XCI-skew is heritable in blood of females >55 years old (h2 = 0.34), but not in younger individuals or other tissues. This results in a Gene x Age interaction that shifts the functional dosage of all X-linked heterozygous loci in a tissue-restricted manner.


Assuntos
Artrite Reumatoide/genética , Cromossomos Humanos X/genética , Genes Ligados ao Cromossomo X/genética , Predisposição Genética para Doença/genética , Gêmeos/genética , Inativação do Cromossomo X , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Feminino , Humanos , Pessoa de Meia-Idade , Especificidade de Órgãos/genética
4.
Dev Psychol ; 55(12): 2575-2586, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31621343

RESUMO

Depression is associated with dietary factors and epigenetics. Serum cholesterol, which is prone to dietary influences, has been linked to symptoms of depression. This relationship may be (in part) due to altered epigenetic regulation of Methylenetetrahydrofolate Reductase (MTHFR). MTHFR codes for the MTHFR enzyme, which has diverse metabolic functions, and has recently been linked individually with diet, serum cholesterol levels and depressive symptoms. In 514 mother-child pairs, we examined prospective relationships between maternal (pregnancy) and child (7 years) serum cholesterol, MTHFR DNA methylation (DNAm; birth, 7 years), and development of depression symptoms from 8-15 years. After adjusting for potential confounding, we had three main findings. First, higher prenatal cholesterol associated (at a small effect size) with higher MTHFR DNAm at birth. Second, there was small effect size continuity for MTHFR DNAm between birth and age 7. Third, higher age 7 MTHFR DNAm associated with higher initial symptoms of depression symptoms at age 8, again at a small effect size. Overall, our findings provide preliminary evidence for a relationship between prenatal cholesterol, MTHFR DNAm, and symptoms of depression in children. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


Assuntos
Colesterol/sangue , Metilação de DNA , Depressão/genética , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Criança , Depressão/psicologia , Epigênese Genética , Feminino , Humanos , Estudos Longitudinais , Masculino , Gravidez , Estudos Prospectivos
5.
Psychol Assess ; 31(8): 1006-1018, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31070449

RESUMO

Questionnaire measures offer a time and cost-effective alternative to full diagnostic assessments for identifying and differentiating between potential anxiety disorders and are commonly used in clinical practice. Little is known, however, about the capacity of questionnaire measures to detect specific anxiety disorders in clinically anxious preadolescent children. This study aimed to establish the ability of the Spence Children's Anxiety Scale (SCAS) subscales to identify children with specific anxiety disorders in a large clinic-referred sample (N = 1,438) of children aged 7 to 12 years. We examined the capacity of the Separation Anxiety, Social Phobia, Generalized Anxiety, and Physical Injury Fears (phobias) subscales to discriminate between children with and without the target disorder. We also identified optimal cutoff scores on subscales for accurate identification of children with the corresponding disorder, and examined the contribution of child, mother, and father reports. The Separation Anxiety subscale was able to accurately identify children with separation anxiety disorder, and this was replicated across all 3 reporters. Mother- and father-reported Social Phobia subscales also accurately identified children with social anxiety disorder, although child report was only able to accurately detect social anxiety disorder in girls. Using 2 or more reporters improved the sensitivity of the Separation Anxiety and Social Phobia subscales but reduced specificity. The Generalized Anxiety and Physical Injury Fears subscales failed to accurately identify children with the corresponding disorders. These findings have implications for the potential use of mother-, father-, and child-report SCAS subscales to detect specific disorders in preadolescent children in clinical settings. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


Assuntos
Transtornos de Ansiedade/diagnóstico , Escalas de Graduação Psiquiátrica/estatística & dados numéricos , Inquéritos e Questionários/estatística & dados numéricos , Criança , Feminino , Humanos , Masculino , Mães , Psicometria , Reprodutibilidade dos Testes , Sensibilidade e Especificidade
6.
Transl Psychiatry ; 9(1): 150, 2019 05 23.
Artigo em Inglês | MEDLINE | ID: mdl-31123309

RESUMO

Major depressive disorder and the anxiety disorders are highly prevalent, disabling and moderately heritable. Depression and anxiety are also highly comorbid and have a strong genetic correlation (rg ≈ 1). Cognitive behavioural therapy is a leading evidence-based treatment but has variable outcomes. Currently, there are no strong predictors of outcome. Therapygenetics research aims to identify genetic predictors of prognosis following therapy. We performed genome-wide association meta-analyses of symptoms following cognitive behavioural therapy in adults with anxiety disorders (n = 972), adults with major depressive disorder (n = 832) and children with anxiety disorders (n = 920; meta-analysis n = 2724). We estimated the variance in therapy outcomes that could be explained by common genetic variants (h2SNP) and polygenic scoring was used to examine genetic associations between therapy outcomes and psychopathology, personality and learning. No single nucleotide polymorphisms were strongly associated with treatment outcomes. No significant estimate of h2SNP could be obtained, suggesting the heritability of therapy outcome is smaller than our analysis was powered to detect. Polygenic scoring failed to detect genetic overlap between therapy outcome and psychopathology, personality or learning. This study is the largest therapygenetics study to date. Results are consistent with previous, similarly powered genome-wide association studies of complex traits.


Assuntos
Transtornos de Ansiedade/genética , Transtornos de Ansiedade/terapia , Terapia Cognitivo-Comportamental/estatística & dados numéricos , Transtorno Depressivo Maior/genética , Transtorno Depressivo Maior/terapia , Estudo de Associação Genômica Ampla/estatística & dados numéricos , Avaliação de Resultados em Cuidados de Saúde/estatística & dados numéricos , Adulto , Criança , Humanos
7.
JAMA Psychiatry ; 76(6): 614-623, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-30916743

RESUMO

Importance: Urbanicity is a well-established risk factor for clinical (eg, schizophrenia) and subclinical (eg, hearing voices and paranoia) expressions of psychosis. To our knowledge, no studies have examined the association of air pollution with adolescent psychotic experiences, despite air pollution being a major environmental problem in cities. Objectives: To examine the association between exposure to air pollution and adolescent psychotic experiences and test whether exposure mediates the association between urban residency and adolescent psychotic experiences. Design, Setting, and Participants: The Environmental-Risk Longitudinal Twin Study is a population-based cohort study of 2232 children born during the period from January 1, 1994, through December 4, 1995, in England and Wales and followed up from birth through 18 years of age. The cohort represents the geographic and socioeconomic composition of UK households. Of the original cohort, 2066 (92.6%) participated in assessments at 18 years of age, of whom 2063 (99.9%) provided data on psychotic experiences. Generation of the pollution data was completed on October 4, 2017, and data were analyzed from May 4 to November 21, 2018. Exposures: High-resolution annualized estimates of exposure to 4 air pollutants-nitrogen dioxide (NO2), nitrogen oxides (NOx), and particulate matter with aerodynamic diameters of less than 2.5 (PM2.5) and less than 10 µm (PM10)-were modeled for 2012 and linked to the home addresses of the sample plus 2 commonly visited locations when the participants were 18 years old. Main Outcomes and Measures: At 18 years of age, participants were privately interviewed regarding adolescent psychotic experiences. Urbanicity was estimated using 2011 census data. Results: Among the 2063 participants who provided data on psychotic experiences, sex was evenly distributed (52.5% female). Six hundred twenty-three participants (30.2%) had at least 1 psychotic experience from 12 to 18 years of age. Psychotic experiences were significantly more common among adolescents with the highest (top quartile) level of annual exposure to NO2 (odds ratio [OR], 1.71; 95% CI, 1.28-2.28), NOx (OR, 1.72; 95% CI, 1.30-2.29), and PM2.5 (OR, 1.45; 95% CI, 1.11-1.90). Together NO2 and NOx statistically explained 60% of the association between urbanicity and adolescent psychotic experiences. No evidence of confounding by family socioeconomic status, family psychiatric history, maternal psychosis, childhood psychotic symptoms, adolescent smoking and substance dependence, or neighborhood socioeconomic status, crime, and social conditions occurred. Conclusions and Relevance: In this study, air pollution exposure-particularly NO2 and NOx-was associated with increased odds of adolescent psychotic experiences, which partly explained the association between urban residency and adolescent psychotic experiences. Biological (eg, neuroinflammation) and psychosocial (eg, stress) mechanisms are plausible.


Assuntos
Poluentes Atmosféricos/efeitos adversos , Poluição do Ar/efeitos adversos , Exposição Ambiental/efeitos adversos , Transtornos Psicóticos/etiologia , Adolescente , Poluentes Atmosféricos/análise , Poluição do Ar/análise , Criança , Feminino , Humanos , Masculino , Dióxido de Nitrogênio/efeitos adversos , Dióxido de Nitrogênio/análise , Óxidos de Nitrogênio/efeitos adversos , Óxidos de Nitrogênio/análise , Material Particulado/efeitos adversos , Material Particulado/análise
8.
Transl Psychiatry ; 9(1): 69, 2019 02 04.
Artigo em Inglês | MEDLINE | ID: mdl-30718501

RESUMO

Childhood psychotic experiences (PEs), such as seeing or hearing things that others do not, or extreme paranoia, are relatively common with around 1 in 20 children reporting them at age 12. Childhood PEs are often distressing and can be predictive of schizophrenia, other psychiatric disorders, and suicide attempts in adulthood, particularly if they persist during adolescence. Previous research has demonstrated that methylomic signatures in blood could be potential biomarkers of psychotic phenomena. This study explores the association between DNA methylation (DNAm) and the emergence, persistence, and remission of PEs in childhood and adolescence. DNAm profiles were obtained from the ALSPAC cohort at birth, age 7, and age 15/17 (n = 901). PEs were assessed through interviews with participants at ages 12 and 18. We identified PE-associated probes (p < 5 × 10-5) and regions (corrected p < 0.05) at ages 12 and 18. Several of the differentially methylated probes were also associated with the continuity of PEs across adolescence. One probe (cg16459265), detected consistently at multiple timepoints in the study sample, was replicated in an independent sample of twins (n = 1658). Six regions, including those spanning the HLA-DBP2 and GDF7 genes, were consistently differentially methylated at ages 7 and 15-17. Findings from this large, population-based study suggest that DNAm at multiple stages of development may be associated with PEs in late childhood and adolescence, though further replication is required. Research uncovering biomarkers associated with pre-clinical PEs is important as it has the potential to facilitate early identification of individuals at increased risk who could benefit from preventive interventions.


Assuntos
Metilação de DNA , Transtornos Psicóticos/metabolismo , Adolescente , Criança , Ilhas de CpG , Epigênese Genética/genética , Feminino , Ontologia Genética , Estudos de Associação Genética , Humanos , Recém-Nascido , Estudos Longitudinais , Masculino , Transtornos Psicóticos/sangue , Reino Unido
9.
Psychiatry Res ; 272: 8-17, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30576995

RESUMO

Air pollution is a worldwide environmental health issue. Increasingly, reports suggest that poor air quality may be associated with mental health problems, but these studies often use global measures and rarely focus on early development when psychopathology commonly emerges. To address this, we combined high-resolution air pollution exposure estimates and prospectively-collected phenotypic data to explore concurrent and longitudinal associations between air pollutants of major concern in urban areas and mental health problems in childhood and adolescence. Exploratory analyses were conducted on 284 London-based children from the Environmental Risk (E-Risk) Longitudinal Twin Study. Exposure to annualized PM2.5 and NO2 concentrations was estimated at address-level when children were aged 12. Symptoms of anxiety, depression, conduct disorder, and attention-deficit hyperactivity disorder were assessed at ages 12 and 18. Psychiatric diagnoses were ascertained from interviews with the participants at age 18. We found no associations between age-12 pollution exposure and concurrent mental health problems. However, age-12 pollution estimates were significantly associated with increased odds of major depressive disorder at age 18, even after controlling for common risk factors. This study demonstrates the potential utility of incorporating high-resolution pollution estimates into large epidemiological cohorts to robustly investigate associations between air pollution and youth mental health.


Assuntos
Poluentes Atmosféricos/análise , Poluição do Ar/análise , Transtornos Mentais/epidemiologia , Dióxido de Nitrogênio/análise , Material Particulado/análise , Adolescente , Poluentes Atmosféricos/efeitos adversos , Poluição do Ar/efeitos adversos , Criança , Feminino , Humanos , Londres/epidemiologia , Estudos Longitudinais , Masculino , Transtornos Mentais/induzido quimicamente , Dióxido de Nitrogênio/efeitos adversos , Material Particulado/efeitos adversos
10.
Am J Med Genet B Neuropsychiatr Genet ; 180(2): 150-158, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30334356

RESUMO

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.


Assuntos
Agorafobia/genética , Terapia Implosiva/métodos , Proteínas de Ligação a Tacrolimo/genética , Adulto , Idoso , Agorafobia/terapia , Terapia Cognitivo-Comportamental/métodos , Metilação de DNA/genética , Epigênese Genética/genética , Feminino , Genótipo , Humanos , Sistema Hipotálamo-Hipofisário/metabolismo , Íntrons/genética , Masculino , Pessoa de Meia-Idade , Sistema Hipófise-Suprarrenal/metabolismo , Polimorfismo de Nucleotídeo Único/genética , Regiões Promotoras Genéticas/genética , Proteínas de Ligação a Tacrolimo/metabolismo , Resultado do Tratamento
11.
Curr Opin Psychol ; 27: 13-17, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30077874

RESUMO

The recent interest in epigenetics within mental health research, from a developmental perspective, stems from the potential of DNA methylation to index both exposure to adversity and vulnerability for mental health problems. Genome-wide technology has facilitated epigenome-wide association studies (EWAS), permitting 'hypothesis-free' examinations in relation to adversity and/or mental health problems. In EWAS, rather than focusing on a priori established candidate genes, the genome is screened for DNA methylation, thereby enabling a more comprehensive representation of variation associated with complex disease. Despite their 'hypothesis-free' label, however, results of EWAS are in fact conditional on several a priori hypotheses, dictated by the design of EWAS platforms as well as assumptions regarding the relevance of the biological tissue for mental health phenotypes. In this short report, we review three hidden hypotheses - and provide recommendations - that combined will be useful in designing and interpreting EWAS projects.


Assuntos
Epigenômica , Estudo de Associação Genômica Ampla , Transtornos Mentais/genética , Metilação de DNA/genética , Humanos , Transtornos Mentais/sangue , Fenótipo
12.
Mol Med ; 24(1): 7, 2018 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-30134813

RESUMO

BACKGROUND: In order to retrieve episodic past events, the missing information needs to be reconstructed using information stored in semantic memory. Failures in these reconstructive processes are expressed as false memories. KIBRA single nucleotide polymorphism (rs17070145) has been linked to episodic memory performance as well as an increased risk of Alzheimer's disease and post-traumatic stress disorder (PTSD). METHODS: Here, the role of KIBRA rs17070145 polymorphism (male and female CC vs. CT/TT carriers) in reconstructive episodic memory in the Deese-Roediger-McDermott (DRM) paradigm was investigated in N = 219 healthy individuals. RESULTS: Female participants outperformed males in the free recall condition. Furthermore, a trend towards a gender x genotype interaction was found for false recognition rates. Female CT/TT carriers exhibited a lower proportion of false recognition rates for associated critical lures as compared to male CT/TT. Additionally, an association between KIBRA rs17070145 genotype, familiarity and recollection based recognition performance was found. In trials with correct recognition of listed items CT/TT carriers showed more "remember", but fewer "know" responses as compared to CC carriers. DISCUSSION AND CONCLUSION: Our findings suggest that the T-allele of KIBRA rs17070145 supports recollection based episodic memory retrieval and contributes to memory accuracy in a gender dependent manner. Findings are discussed in the context of the specific contribution of KIBRA related SNPs to reconstructive episodic memory and its implications for cognitive and emotional symptoms in dementia and PTSD.


Assuntos
Peptídeos e Proteínas de Sinalização Intracelular/genética , Memória Episódica , Fosfoproteínas/genética , Adulto , Feminino , Genótipo , Humanos , Masculino , Polimorfismo de Nucleotídeo Único , Adulto Jovem
13.
Dev Psychopathol ; 30(3): 1145-1156, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-30068408

RESUMO

In 785 mother-child (50% male) pairs from a longitudinal epidemiological birth cohort, we investigated associations between inflammation-related epigenetic polygenic risk scores (i-ePGS), environmental exposures, cognitive function, and child and adolescent internalizing and externalizing problems. We examined prenatal and postnatal effects. For externalizing problems, one prenatal effect was found: i-ePGS at birth associated with higher externalizing problems (ages 7-15) indirectly through lower cognitive function (age 7). For internalizing problems, we identified two effects. For a prenatal effect, i-ePGS at birth associated with higher internalizing symptoms via continuity in i-ePGS at age 7. For a postnatal effect, higher postnatal adversity exposure (birth through age 7) associated with higher internalizing problems (ages 7-15) via higher i-ePGS (age 7). Hence, externalizing problems were related mainly to prenatal effects involving lower cognitive function, whereas internalizing problems appeared related to both prenatal and postnatal effects. The present study supports a link between i-ePGS and child and adolescent mental health.


Assuntos
Transtornos do Comportamento Infantil/etiologia , Inflamação/complicações , Saúde Mental , Adolescente , Criança , Feminino , Humanos , Masculino , Gravidez , Estudos Prospectivos , Fatores de Risco
14.
J Child Psychol Psychiatry ; 59(7): 763-772, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29520926

RESUMO

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.


Assuntos
Transtornos de Ansiedade/terapia , Terapia Cognitivo-Comportamental/métodos , Avaliação de Processos e Resultados em Cuidados de Saúde , Pais , Psicoterapia de Grupo/métodos , Ansiedade de Separação/terapia , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Fobia Social/terapia , Transtornos Fóbicos/terapia , Indução de Remissão , Índice de Gravidade de Doença
15.
Eur Arch Psychiatry Clin Neurosci ; 268(3): 261-268, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28364268

RESUMO

Dopamine D2 receptors (DRD2) have been strongly implicated in reward processing of natural stimuli and drugs. Using the approach-avoidance task (AAT), we recently demonstrated that smokers show an increased approach-bias toward smoking-related cues but not toward naturally rewarding stimuli. Here, we examined the contribution of the DRD2 Taq1B polymorphism to smokers' and non-smokers' responsivity toward smoking versus naturally rewarding stimuli in the AAT. Smokers carrying the minor B1 allele of the DRD2 Taq1B polymorphism showed reduced approach behavior for food-related pictures compared to non-smokers with the same allele. In the group of smokers, a higher approach-bias toward smoking-related compared to food-related pictures was found in carriers of the B1 allele. This pattern was not evident in smokers homozygous for the B2 allele. In addition, smokers with the B1 allele reported fewer attempts to quit smoking relative to smokers homozygous for the B2 allele. This is the first study demonstrating that behavioral shifts in response to smoking relative to natural rewards in smokers are mediated by the DRD2 Taq1B polymorphism. Our results indicate a reduced natural-reward brain reactivity in smokers with a genetically determined decrease in dopaminergic activity (i.e., reduction of DRD2 availability). It remains to be determined whether this pattern might be related to a different outcome after psychological cessation interventions, i.e., AAT modification paradigms, in smokers.


Assuntos
Aprendizagem da Esquiva/fisiologia , Predisposição Genética para Doença/genética , Polimorfismo de Nucleotídeo Único/genética , Receptores de Dopamina D2/genética , Recompensa , Fumar/genética , Adulto , Feminino , Frequência do Gene , Genótipo , Humanos , Masculino , Autorrelato , Fumar/psicologia , Adulto Jovem
16.
Am J Med Genet B Neuropsychiatr Genet ; 174(2): 144-155, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-27346075

RESUMO

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.


Assuntos
Transtornos de Ansiedade/genética , Endocanabinoides/genética , Adolescente , Amidoidrolases/genética , Amidoidrolases/metabolismo , Ansiedade/genética , Criança , Terapia Cognitivo-Comportamental/métodos , Endocanabinoides/metabolismo , Medo/psicologia , Feminino , Variação Genética/genética , Humanos , Masculino , Polimorfismo de Nucleotídeo Único/genética , Receptor CB1 de Canabinoide/genética , Receptor CB1 de Canabinoide/metabolismo , Receptor CB2 de Canabinoide/genética , Receptor CB2 de Canabinoide/metabolismo , Resultado do Tratamento
17.
World J Biol Psychiatry ; 18(3): 215-226, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-27376411

RESUMO

OBJECTIVES: Exposure-based cognitive behavioural therapy (eCBT) is an effective treatment for anxiety disorders. Response varies between individuals. Gene expression integrates genetic and environmental influences. We analysed the effect of gene expression and genetic markers separately and together on treatment response. METHODS: Adult participants (n ≤ 181) diagnosed with panic disorder or a specific phobia underwent eCBT as part of standard care. Percentage decrease in the Clinical Global Impression severity rating was assessed across treatment, and between baseline and a 6-month follow-up. Associations with treatment response were assessed using expression data from 3,233 probes, and expression profiles clustered in a data- and literature-driven manner. A total of 3,343,497 genetic variants were used to predict treatment response alone and combined in polygenic risk scores. Genotype and expression data were combined in expression quantitative trait loci (eQTL) analyses. RESULTS: Expression levels were not associated with either treatment phenotype in any analysis. A total of 1,492 eQTLs were identified with q < 0.05, but interactions between genetic variants and treatment response did not affect expression levels significantly. Genetic variants did not significantly predict treatment response alone or in polygenic risk scores. CONCLUSIONS: We assessed gene expression alone and alongside genetic variants. No associations with treatment outcome were identified. Future studies require larger sample sizes to discover associations.


Assuntos
Terapia Cognitivo-Comportamental/métodos , Terapia Implosiva/métodos , Transtorno de Pânico/genética , Transtorno de Pânico/terapia , Transtornos Fóbicos/genética , Transtornos Fóbicos/terapia , Adulto , Feminino , Expressão Gênica , Marcadores Genéticos , Variação Genética , Estudo de Associação Genômica Ampla , Genótipo , Alemanha , Humanos , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Fenótipo , Resultado do Tratamento
18.
Psychother Psychosom ; 85(3): 146-58, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27043157

RESUMO

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.


Assuntos
Transtornos de Ansiedade/genética , Transtornos de Ansiedade/terapia , Terapia Cognitivo-Comportamental/métodos , Estudo de Associação Genômica Ampla , Herança Multifatorial , Poder Familiar , Criança , Feminino , Predisposição Genética para Doença , Humanos , Modelos Lineares , Modelos Logísticos , Masculino , Saúde Mental
19.
Br J Psychiatry ; 209(3): 236-43, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-26989097

RESUMO

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.


Assuntos
Transtornos de Ansiedade/genética , Terapia Cognitivo-Comportamental , Estudo de Associação Genômica Ampla , Adolescente , Transtornos de Ansiedade/terapia , Criança , Pré-Escolar , Feminino , Genótipo , Humanos , Masculino , Polimorfismo de Nucleotídeo Único/genética , Resultado do Tratamento
20.
Br J Psychiatry ; 208(2): 182-8, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26294368

RESUMO

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.


Assuntos
Transtornos de Ansiedade/genética , Transtornos de Ansiedade/terapia , Terapia Cognitivo-Comportamental , Interação Gene-Ambiente , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética , Adolescente , Alelos , Criança , Pré-Escolar , Feminino , Genótipo , Humanos , Masculino , Escalas de Graduação Psiquiátrica , Indução de Remissão , Resultado do Tratamento
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