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Background: Children and adolescents demonstrate diverse patterns of symptom change and disorder remission following cognitive behavioural therapy (CBT) for anxiety disorders. To better understand children who respond sub-optimally to CBT, this study investigated youths (N = 1,483) who continued to meet criteria for one or more clinical anxiety diagnosis immediately following treatment or at any point during the 12 months following treatment., Methods: Data were collected from 10 clinical sites with assessments at pre-and post-treatment and at least once more at 3, 6 or 12-month follow-up. Participants were assigned to one of three groups based on diagnostic status for youths who: (a) retained an anxiety diagnosis from post to end point (minimal responders); (b) remitted anxiety diagnoses at post but relapsed by end point (relapsed responders); and (c) retained a diagnosis at post but remitted to be diagnosis free at end point (delayed responders). Growth curve models assessed patterns of change over time for the three groups and examined predictors associated with these patterns including demographic, clinical and parental factors, as well as treatment factors., Results: Higher primary disorder severity, being older, having a greater number of anxiety disorders, having social anxiety disorder, as well as higher maternal psychopathology differentiated the minimal responders from the delayed and relapsed responders at the baseline. Results from the growth curve models showed that severity of the primary disorder and treatment modality differentiated patterns of linear change only. Higher severity was associated with significantly less improvement over time for the minimal and relapsed response groups, as was receiving group CBT, when compared to the delayed response group., Conclusions: Sub-optimal response patterns can be partially differentiated using variables assessed at pre-treatment. Increased understanding of different patterns of change following treatment may provide direction for clinical decision-making and for tailoring treatments to specific groups of clinically anxious youth. Future research may benefit from assessing progress during treatment to detect emerging response patterns earlier., (© 2024 The Author(s). Journal of Child Psychology and Psychiatry published by John Wiley & Sons Ltd on behalf of Association for Child and Adolescent Mental Health.)

Underlying classes capture differences between patient symptom trajectories during psychological therapy. This has not been explored for one-to-one internet-delivered therapy or functional impairment trajectories. Patients experiencing depression or anxiety received cognitive-behavioural therapy with a therapist using an online chat platform (N = 52,029). Trajectory classes of depression symptoms (PHQ9), anxiety symptoms (GAD7) and functional impairment (WSAS) were investigated using growth mixture modelling. Multinomial regressions tested associations between baseline variables and trajectory class. A four-class trajectory model was selected for each outcome, and these were highly similar. Each outcome showed three classes with initially moderate-severe symptoms or impairment: one demonstrated no change, one gradual improvement and one fast improvement. A fourth class had mild baseline scores and minimal improvement. In the moderate-severe classes, patients in the two with improvement were more likely to be employed and not to have obsessive-compulsive disorder. Fast improvement was likelier than gradual improvement or no change for patients with older age, no disability (e.g., physical, learning), or lower comorbid symptom or impairment scores. Associations with functional impairment classes were more similar to associations with depression classes than anxiety classes. Results were largely consistent with findings from face-to-face therapy. This study is an important step towards personalising therapy in terms of suitability and continuation., Competing Interests: Declaration of competing interest Ana Catarino and Stephanie Brown are employees of ieso, the company who provided the therapy for NHS patients and shared the anonymised patient data for analysis. All other authors declare no conflict of interest., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

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., Competing Interests: Conflict of Interest AR reports speaker honoraria and advisory board honoraria from Janssen, Servier, Medice, Shire and neuraxpharm. VA has received compensations for his contributions as member of advisory boards and for presentations for the following companies: Astra-Zeneca, Eli Lilly, Janssen-Cilag, Lundbeck, Otsuka, Sanofi, Servier, and Trommsdorff. TCE is part funded by a program grant from the UK Medical Research Council (MR/M021475/1), and the National Institute for Health Research (NIHR) Biomedical Research center at South London and Maudsley NHS Foundation Trust and King's College London. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. PP reports having received research funding from Volkswagenstiftung (A124277) and that he is shareholder of a commercial company (VTplus) that develops virtual reality research systems. KD is a member of the Janssen Pharmaceuticals, Inc. Steering Committee Neurosciences. All other authors reported no biomedical financial interests or potential conflicts of interest., (Copyright © 2021. Published by Elsevier B.V.)

Objective/background: Many patients find cognitive behavioral therapy for insomnia (CBT-I) useful. However, it is currently unknown if those with sub-threshold insomnia also benefit. Here we assessed whether CBT-I is both feasible and acceptable in participants with sub-threshold insomnia. The primary aims were to evaluate participation rates and treatment acceptability, and to establish an effect size for symptom improvement., Patients/methods: A total of 199 female participants (M age 20 ± 5 years) took part. Following baseline assessments, participants were randomly allocated to either a six-week digital CBT-I intervention or a six-week control group receiving puzzles. Additional assessments were performed three-weeks, six-weeks, and six-months later., Results: Participation rates at each survey assessment wave did not differ between the groups (ps > 0.140), though adherence to completing each weekly task was lower in the CBT-I group, p = 0.02. Treatment acceptability was high (M (SD) = 33.61 (4.82), theoretical range 6-42). The CBT-I group showed greater improvement in insomnia symptoms at the end of the intervention compared to the control group (p = 0.013, d = 0.42), with significant variation in outcome (M = 4.69, SD = 5.41). Sub-threshold participants showed a similar pattern of results, whilst those meeting insomnia criteria showed a smaller between-group difference. CBT-I led to improvements in anxiety, paranoia and perceived stress between baseline and end of intervention. Changes in insomnia symptoms were mediated by cognitions about sleep and somatic pre-sleep arousal., Conclusions: CBT-I provides a benefit even in sub-threshold insomnia. CBT-I may be useful to tackle insomnia symptoms even when they are sub-threshold., (Copyright © 2019 Elsevier B.V. All rights reserved.)

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 (r g  ≈ 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 (h 2 SNP ) 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 h 2 SNP 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.

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., (© 2018 The Authors. Journal of Child Psychology and Psychiatry published by John Wiley & Sons Ltd on behalf of Association for Child and Adolescent Mental Health.)

Introduction: Cognitive-behavioural therapy for insomnia (CBT-I) leads to insomnia symptom improvements in a substantial proportion of patients. However, not everyone responds well to this treatment, and it is unclear what determines individual differences in response. The broader aim of this work is to examine to what extent response to CBT-I is due to genetic and environmental factors. The purpose of this pilot study is to examine feasibility of a design to test hypotheses focusing on an unselected sample, that is, without selection on insomnia complaints, in order to plan a larger behavioural genetics study where most participants will likely not have an insomnia disorder., Methods and Analysis: A two parallel-group randomised controlled trial is being conducted across three London universities. Female students (minimum age 18 years) enrolled on a psychology programme at one of the three sites were invited to participate. The target number of participants to be recruited is 240. Following baseline assessments, participants were randomly allocated to either the treatment group, where they received weekly sessions of digital CBT-I for 6 weeks, or the control group, where they completed an online puzzle each week for 6 weeks. Follow-up assessments have taken place mid-intervention (3 weeks) and end of intervention (6 weeks). A 6-month follow-up assessment will also occur. Primary outcomes will be assessed using descriptive statistics and effect size estimates for intervention effects. Secondary outcomes will be analysed using multivariate generalised estimating equation models., Ethics and Dissemination: The study received ethical approval from the Research Ethics and Integrity subcommittee, Goldsmiths, University of London (application reference: EA 1305). DNA sample collection for the BioResource received ethical approval from the NRES Committee South Central-Oxford (reference number: 15/SC/0388). The results of this work shall be published in peer-reviewed journals., Trial Registration Number: NCT03062891; Results., Competing Interests: Competing interests: The position of AIL at the University of Oxford is funded by Big Health Ltd, the company behind the digital CBT-I programme evaluated in this study. CAE is the cofounder and CMO of Big Health Ltd and holds shares in Big Health Ltd. AMG has provided guidance and educational content for a freely available educational website focused on infant sleep. This website is partially supported by Johnson and Johnson, but they do not have any influence over content and do not advertise on it. AMG also contributes to BBC Focus Magazine., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

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.

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., Competing Interests: Declaration of interest R.M.R., J.L.H. and H.J.L. are co-authors of the Cool Kids program but receive no direct payments. C. Creswell is co-author of books in the ’Overcoming’ series and receives royalties. W.K.S. is author of the Anxiety Disorders Interview Schedule for Children and receives royalties. G.B. is a consultant in pre-clinical genetics for Eli Lilly., (© The Royal College of Psychiatrists 2016.)

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., (© The Royal College of Psychiatrists 2016.)

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., (© 2016 S. Karger AG, Basel.)

Background: Hypothalamic-pituitary-adrenal (HPA) axis functioning has been implicated in the development of stress-related psychiatric diagnoses and response to adverse life experiences. This study aimed to investigate the association between genetic and epigenetics in HPA axis and response to cognitive behavior therapy (CBT)., Methods: Children with anxiety disorders were recruited into the Genes for Treatment project (GxT, N = 1,152). Polymorphisms of FKBP5 and GR were analyzed for association with response to CBT. Percentage DNA methylation at the FKBP5 and GR promoter regions was measured before and after CBT in a subset (n = 98). Linear mixed effect models were used to investigate the relationship between genotype, DNA methylation, and change in primary anxiety disorder severity (treatment response)., Results: Treatment response was not associated with FKBP5 and GR polymorphisms, or pretreatment percentage DNA methylation. However, change in FKBP5 DNA methylation was nominally significantly associated with treatment response. Participants who demonstrated the greatest reduction in severity decreased in percentage DNA methylation during treatment, whereas those with little/no reduction in severity increased in percentage DNA methylation. This effect was driven by those with one or more FKBP5 risk alleles, with no association seen in those with no FKBP5 risk alleles. No significant association was found between GR methylation and response., Conclusions: Allele-specific change in FKBP5 methylation was associated with treatment response. This is the largest study to date investigating the role of HPA axis related genes in response to a psychological therapy. Furthermore, this is the first study to demonstrate that DNA methylation changes may be associated with response to psychological therapies in a genotype-dependent manner., (© 2015 The Authors. Depression and Anxiety published by Wiley Periodicals, Inc.)

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., (Copyright © 2015 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.)

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.

Background: Within a therapeutic gene by environment (G × E) framework, we recently demonstrated that variation in the Serotonin Transporter Promoter Polymorphism; 5HTTLPR and marker rs6330 in Nerve Growth Factor gene; NGF is associated with poorer outcomes following cognitive behaviour therapy (CBT) for child anxiety disorders. The aim of this study was to explore one potential means of extending the translational reach of G × E data in a way that may be clinically informative. We describe a 'risk-index' approach combining genetic, demographic and clinical data and test its ability to predict diagnostic outcome following CBT in anxious children., Method: DNA and clinical data were collected from 384 children with a primary anxiety disorder undergoing CBT. We tested our risk model in five cross-validation training sets., Results: In predicting treatment outcome, six variables had a minimum mean beta value of 0.5:5HTTLPR, NGF rs6330, gender, primary anxiety severity, comorbid mood disorder and comorbid externalising disorder. A risk index (range 0-8) constructed from these variables had moderate a predictive ability (AUC = .62-.69) in this study. Children scoring high on this index (5-8) were approximately three times as likely to retain their primary anxiety disorder at follow-up as compared with those children scoring 2 or less., Conclusion: Significant genetic, demographic and clinical predictors of outcome following CBT for anxiety-disordered children were identified. Combining these predictors within a risk index could be used to identify which children are less likely to be diagnosis-free following CBT alone and require longer or enhanced treatment. The 'risk-index' approach represents one means of harnessing the translational potential of G × E data., (© 2013 The Authors. Journal of Child Psychology and Psychiatry © 2013 Association for Child and Adolescent Mental Health.)

Therapygenetics, the study of genetic determinants of response to psychological therapies, is in its infancy. Here, we investigate whether single-nucleotide polymorphisms in nerve growth factor (NGF) (rs6330) and brain-derived neutrotrophic factor (BDNF) (rs6265) genes predict the response to cognitive behaviour therapy (CBT). Neurotrophic genes represent plausible candidate genes: they are implicated in synaptic plasticity, response to stress, and are widely expressed in brain areas involved in mood and cognition. Allelic variation at both loci has shown associations with anxiety-related phenotypes. A sample of 374 anxiety-disordered children with white European ancestry was recruited from clinics in Reading, UK, and in Sydney, Australia. Participants received manualised CBT treatment and DNA was collected from buccal cells using cheek swabs. Treatment response was assessed at post-treatment and follow-up time points. We report first evidence that children with one or more copies of the T allele of NGF rs6330 were significantly more likely to be free of their primary anxiety diagnosis at follow-up (OR = 0.60 (0.42-0.85), P = 0.005). These effects remained even when other clinically relevant covariates were accounted for (OR = 0.62 (0.41-0.92), P = 0.019). No significant associations were observed between BDNF rs6265 and response to psychological therapy. These findings demonstrate that knowledge of genetic markers has the potential to inform clinical treatment decisions for psychotherapeutic interventions.