Susanna Roberts

Clinical Predictors of Response to Cognitive-Behavioral Therapy in Pediatric Anxiety Disorders: The Genes for Treatment (GxT) Study

Objective The Genes for Treatment study is an international, multisite collaboration exploring the role of genetic, demographic, and clinical predictors in response to cognitive-behavioral therapy (CBT) in pediatric anxiety disorders. The current article, the first from the study, examined demographic and clinical predictors of response to CBT. We hypothesized that the child’s gender, type of anxiety disorder, initial severity and comorbidity, and parents’ psychopathology would significantly predict outcome. Method A sample of 1,519 children 5 to 18 years of age with a primary anxiety diagnosis received CBT across 11 sites. Outcome was defined as response (change in diagnostic severity) and remission (absence of the primary diagnosis) at each time point (posttreatment, 3-, 6-, and/or 12-month follow-up) and analyzed using linear and logistic mixed models. Separate analyses were conducted using data from posttreatment and follow-up assessments to explore the relative importance of predictors at these time points. Results Individuals with social anxiety disorder (SoAD) had significantly poorer outcomes (poorer response and lower rates of remission) than those with generalized anxiety disorder (GAD). Although individuals with specific phobia (SP) also had poorer outcomes than those with GAD at posttreatment, these differences were not maintained at follow-up. Both comorbid mood and externalizing disorders significantly predicted poorer outcomes at posttreatment and follow-up, whereas self-reported parental psychopathology had little effect on posttreatment outcomes but significantly predicted response (although not remission) at follow-up. Conclusion SoAD, nonanxiety comorbidity, and parental psychopathology were associated with poorer outcomes after CBT. The results highlight the need for enhanced treatments for children at risk for poorer outcomes.

Serotonin tranporter methylation and response to cognitive behaviour therapy in children with anxiety disorders

Anxiety disorders that are the most commonly occurring psychiatric disorders in childhood, are associated with a range of social and educational impairments and often continue into adulthood. Cognitive behaviour therapy (CBT) is an effective treatment option for the majority of cases, although up to 35–45% of children do not achieve remission. Recent research suggests that some genetic variants may be associated with a more beneficial response to psychological therapy. Epigenetic mechanisms such as DNA methylation work at the interface between genetic and environmental influences. Furthermore, epigenetic alterations at the serotonin transporter (SERT) promoter region have been associated with environmental influences such as stressful life experiences. In this study, we measured DNA methylation upstream of SERT in 116 children with an anxiety disorder, before and after receiving CBT. Change during treatment in percentage DNA methylation was significantly different in treatment responders vs nonresponders. This effect was driven by one CpG site in particular, at which responders increased in methylation, whereas nonresponders showed a decrease in DNA methylation. This is the first study to demonstrate differences in SERT methylation change in association with response to a purely psychological therapy. These findings confirm that biological changes occur alongside changes in symptomatology following a psychological therapy such as CBT.

HPA AXIS RELATED GENES AND RESPONSE TO PSYCHOLOGICAL THERAPIES: GENETICS AND EPIGENETICS.

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).

Non-replication of the association between 5HTTLPR and response to psychological therapy for child anxiety disorders

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.

Genome-wide association study of response to cognitive–behavioural therapy in children with anxiety disorders

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.

Genetic variation in the endocannabinoid system and response to Cognitive Behavior Therapy for child anxiety disorders

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.

Genome-wide expression and response to exposure-based psychological therapy for anxiety disorders

Exposure-based psychological treatments for anxiety have high efficacy. However, a substantial proportion of patients do not respond to therapy. Research examining the potential biological underpinnings of therapy response is still in its infancy, and most studies have focussed on candidate genes. To our knowledge, this study represents the first investigation of genome-wide expression profiles with respect to treatment outcome. Participants (n=102) with panic disorder or specific phobia received exposure-based cognitive behavioural therapy. Treatment outcome was defined as percentage reduction from baseline in clinician-rated severity of their primary anxiety diagnosis at post treatment and 6 month follow-up. Gene expression was determined from whole blood samples at three time points using the Illumina HT-12v4 BeadChip microarray. Linear regression models tested the association between treatment outcome and changes in gene expression from pre-treatment to post treatment, and pre-treatment to follow-up. Network analysis was conducted using weighted gene co-expression network analysis, and change in the detected modules from pre-treatment to post treatment and follow-up was tested for association with treatment outcome. No changes in gene expression were significantly associated with treatment outcomes when correcting for multiple testing (q<0.05), although a small number of genes showed a suggestive association with treatment outcome (q<0.5, n=20). Network analysis showed no association between treatment outcome and change in gene expression for any module. We report suggestive evidence for the role of a small number of genes in treatment outcome. Although preliminary, these findings contribute to a growing body of research suggesting that response to psychological therapies may be associated with changes at a biological level.

The dopamine D2 receptor mediates approach-avoidance tendencies in smokers

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.

Separate and combined effects of genetic variants and pre-treatment whole blood gene expression on response to exposure-based cognitive behavioural therapy for anxiety disorders

Abstract 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.

16.1 EPIGENETIC SIGNATURES OF CHILDHOOD AND ADOLESCENT VICTIMISATION USING A GENETICALLY SENSITIVE LONGITUDINAL COHORT STUDY.

Abstract Background Stress is a normal, adaptive response to stressors (e.g. events that make a person feel threatened or upset). However, healthy development can be derailed by excessive or prolonged exposure to stress especially during important developmental periods such as childhood and adolescence. Exposure to severe stress may have immediate as well as long-lasting damaging effects on learning, behaviour, and health, and has been implicated in the development of psychosis. One way these may occur is via changes to epigenetic processes (e.g. alterations in DNA methylation). Initial studies have shown that individuals exposed to severe psychosocial stress have different patterns of DNA methylation (epigenetic ‘signatures’) compared to individuals exposed to no/minimal stressful life events, but these studies are methodologically limited. Methods This paper describes our examination of the potential link between exposure to multiple forms of severe victimisation (poly-victimisation) during childhood adolescence and DNA methylation differences utilising data from the Environmental Risk (E-Risk) Longitudinal Twin Study, an epidemiological study of 2,232 children (1,116 twin pairs) born in 1994–1995 in England and Wales and followed to 18 years of age (with 93% retention). Multiple forms of victimisation were ascertained in childhood and adolescence (including physical, sexual and emotional abuse, neglect, exposure to intimate-partner violence, bullying, cyber- and crime victimization) by combining the best practices in survey research with comprehensive interview-based approaches. Whole blood samples were collected from participants at age 18, and the extracted DNA was used to quantify genome-wide patterns of DNA methylation. Results Epigenome-wide analyses of poly-victimisation across childhood and adolescence revealed several significant associations with DNA methylation in peripheral blood at age 18 years, but these were confounded by tobacco smoking and/or did not survive co-twin control tests. Secondary analyses of specific forms of victimisation revealed sparse associations with DNA methylation that did not replicate across different operationalisations of the same putative victimization experience. Hypothesis-driven analyses of six candidate genes in the stress response (NR3C1, FKBP5, BDNF, AVP, CRHR1, SLC6A4) did not reveal predicted associations with DNA methylation in probes annotated to these genes. Discussion Findings from this epidemiological analysis of the epigenetic effects of early-life stress do not support the hypothesis of robust changes in DNA methylation in victimised young people. It is possible that epigenetic epidemiology is not yet well matched to experimental, non-human models in uncovering the biological embedding of stress.