Patterns of sub-optimal change following CBT for childhood anxiety.

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.

Changes to sleep patterns and insomnia symptoms following cognitive behavioural therapy for anxiety disorders in adolescents.

BACKGROUND: It is unclear whether treatment for an anxiety disorder improves sleep. This study examined baseline sleep characteristics of adolescents with an anxiety disorder, comparing weekdays and weekends, and whether there were significant improvements in sleep following cognitive behaviour therapy (CBT). AIMS: To improve our understanding of sleep problems in adolescents with an anxiety disorder and examine whether CBT for the treatment of the anxiety disorder improves sleep. METHOD: Data was gathered from 179 participants with an anxiety disorder (11-17 years old) who had previously engaged with the out-patient child and adolescent mental health service. Baseline self-report measures of anxiety and depression symptoms, sleep patterns and experiences of insomnia were examined. Of this group, 135 participants had baseline data. A subset (n=73) had outcome data, which was used to examine changes in sleep following CBT. RESULTS: At baseline, adolescents reported significantly less total sleep and more night-time waking on weekdays than weekends. Following treatment for their anxiety disorder, adolescents' weekday sleep patterns significantly improved for sleep onset latency and total sleep time, whereas weekend sleep patterns only showed improvements for sleep onset latency. No significant improvements were reported for symptoms of insomnia. CONCLUSIONS: The study relied upon subjective measurement of sleep and there was no control group; however, the findings provide promising results that CBT for adolescent anxiety disorders can improve some sleep problems. Further research is needed to understand discrepancies between subjective and objective sleep, and to explore avenues for the delivery of support for sleep problems.

Measuring dissociation across adolescence and adulthood: developing the short-form Cernis Felt Sense of Anomaly scale (CEFSA-14).

BACKGROUND: Dissociation may be important across many mental health disorders, but has been variously conceptualised and measured. We introduced a conceptualisation of a common type of dissociative experience, 'felt sense of anomaly' (FSA), and developed a corresponding measure, the Cernis Felt Sense of Anomaly (CEFSA) scale. AIMS: We aimed to develop a short-form version of the CEFSA that is valid for adolescent and adult respondents. METHOD: Data were collected from 1031 adult NHS patients with psychosis and 932 adult and 1233 adolescent non-clinical online survey respondents. Local structural equation modelling (LSEM) was used to establish measurement invariance of items across the age range. Ant colony optimisation (ACO) was used to produce a 14-item short-form measure. Finally, the expected test score function derived from item response theory modelling guided the establishment of interpretive scoring ranges. RESULTS: LSEM indicated 25 items of the original 35-item CEFSA were age invariant. They were also invariant across gender and clinical status. ACO of these items produced a 14-item short-form (CEFSA-14) with excellent psychometric properties (CFI=0.992; TLI=0.987; RMSEA=0.034; SRMR=0.017; Cronbach's alpha=0.92). Score ranges were established based on the expected test scores at approximately 0.7, 1.25 and 2.0 theta (equivalent to standard deviations above the mean). Scores of 29 and above may indicate elevated levels of FSA-dissociation. CONCLUSIONS: The CEFSA-14 is a psychometrically valid measure of FSA-dissociation for adolescents and adults. It can be used with clinical and non-clinical respondents. It could be used by clinicians as an initial tool to explore dissociation with their clients.

In the moment social experiences and perceptions of children with social anxiety disorder: A qualitative study.

OBJECTIVES: Childhood social anxiety disorder (SAD) is a common and disabling condition. General forms of cognitive behavioural treatments have demonstrated poorer efficacy for childhood SAD when compared to other childhood anxiety disorders and further understanding of the psychological factors that contribute to the maintenance of childhood SAD is warranted. Examining the social experiences of children with SAD may help to identify relevant psychological factors and increase our understanding of what keeps childhood SAD going. METHODS: The current study used reflexive thematic analysis to analyse the transcripts of interviews with 12 children aged 8-12 years with SAD who had been interviewed about their 'in the moment' social experiences during a social stress induction task. The interview topic guide included factors hypothesized to maintain SAD in adult cognitive models of the disorder. RESULTS: The interviews revealed both variety and commonalities in the experiences and interpretations of social events in children with SAD, captured in three related main themes: (i) Discomfort being the centre of attention, (ii) (Lack of) awareness of cognitions and (iii) Managing social fears. Findings indicated likely developmental influences on which maintenance mechanisms apply at which point in time. CONCLUSIONS: There is variation in the psychological mechanisms that children with SAD endorse and developmental factors are likely to influence when specific mechanisms are relevant. We now need further studies that take a developmentally informed approach to understand the nature of the association between the factors identified in this study and social anxiety in childhood to inform the development of more effective interventions for childhood SAD.

The Effectiveness and Cost-Effectiveness of a Universal Digital Parenting Intervention Designed and Implemented During the COVID-19 Pandemic: Evidence From a Rapid-Implementation Randomized Controlled Trial Within a Cohort.

BACKGROUND: Children's conduct and emotional problems increased during the COVID-19 pandemic. OBJECTIVE: We tested whether a smartphone parenting support app, Parent Positive, developed specifically for this purpose, reversed these effects in a cost-effective way. Parent Positive includes 3 zones. Parenting Boosters (zone 1) provided content adapted from standard face-to-face parent training programs to tackle 8 specific challenges identified by parents and parenting experts as particularly relevant for parents during the pandemic. The Parenting Exchange (zone 2) was a parent-to-parent and parent-to-expert communication forum. Parenting Resources (zone 3) provided access to existing high-quality web-based resources on a range of additional topics of value to parents (eg, neurodevelopmental problems, diet, and sleep). METHODS: Supporting Parents And Kids Through Lockdown Experiences (SPARKLE), a randomized controlled trial, was embedded in the UK-wide COVID-19: Supporting Parents, Adolescents and Children during Epidemics (Co-SPACE) longitudinal study on families' mental health during the pandemic. Parents of children aged 4 to 10 years were randomized 1:1 to Parent Positive or follow-up as usual (FAU) between May 19, 2021, and July 26, 2021. Parent Positive provided advice on common parenting challenges and evidence-based web-based resources and facilitated parent-to-parent and expert-to-parent support. Child conduct and emotional problems and family well-being were measured before randomization (T1) and at 1 (T2) and 2 (T3) months after randomization. Service use, costs, and adverse events were measured, along with app use and satisfaction. The primary outcome was T2 parent-reported child conduct problems, which were analyzed using linear mixed regression models. RESULTS: A total of 320 participants were randomized to Parent Positive, and 326 were randomized to FAU. The primary outcome analysis included 79.3% (512/646) of the participants (dropout: 84/320, 26% on Parent Positive and 50/326, 15% on FAU). There were no statistically significant intervention effects on conduct problems at either T2 (standardized effect=-0.01) or T3 (secondary outcome; standardized effect=-0.09) and no moderation by baseline conduct problems. Significant intervention-related reductions in emotional problems were observed at T2 and T3 (secondary outcomes; standardized effect=-0.13 in both cases). Parent Positive, relative to FAU, was associated with more parental worries at T3 (standardized effect=0.14). Few intervention-attributable adverse events were reported. Parent Positive was cost-effective once 4 outliers with extremely high health care costs were excluded. CONCLUSIONS: Parent Positive reduced child emotional problems and was cost-effective compared with FAU once outliers were removed. Although small when considered against targeted therapeutic interventions, the size of these effects was in line with trials of nontargeted universal mental health interventions. This highlights the public health potential of Parent Positive if implemented at the community level. Nevertheless, caution is required before making such an interpretation, and the findings need to be replicated in large-scale, whole-community studies. TRIAL REGISTRATION: ClinicalTrials.gov NCT04786080; https://clinicaltrials.gov/ct2/show/NCT04786080.

The acceptability of a therapist-assisted internet-delivered cognitive behaviour therapy program for the treatment of anxiety disorders in adolescents: a qualitative study.

Computerized treatments have been shown to be effective in young people with anxiety disorders. However, there has been limited investigation into the experiences of adolescents in undertaking this treatment. This qualitative study explored adolescents' experiences of being treated for an anxiety disorder, using an online intervention with therapist support, as part of a randomised controlled trial. Individual semi-structured interviews were conducted with thirteen adolescents aged between 13 and 17 years, who had received the online intervention. Data were analysed using reflexive thematic analysis. Two cross-cutting themes were identified: (i) Usability of the program, and (ii) Putting techniques into practice. Although the convenience of online sessions was recognised as positive, many of the adolescents expressed a preference for face-to-face sessions. The length of sessions and the large amount of reading involved was highlighted by most participants. The transdiagnostic nature of the content meant some elements of the programme were seen as less relevant. While many participants appreciated the 'fun' aspect of the program, others felt that certain aspects of the program were not suitable for their age group. Exposure, psychoeducation and cognitive restructuring were generally received positively, whereas responses to the use of relaxation and rewards were much more mixed. Our findings highlight the potential utility for online treatments delivered with therapist support. However, they also highlight how issues with both the format and treatment components can impact the acceptability of a program. As such, further work is warranted to improve the acceptability of online treatments for adolescents with anxiety disorders.

Adolescents' perceived barriers and facilitators to seeking and accessing professional help for anxiety and depressive disorders: a qualitative interview study.

Anxiety and depressive disorders are the most common mental health disorders in adolescents, yet only a minority of young people with these disorders access professional help. This study aims to address this treatment gap by improving our understanding of barriers and facilitators to seeking/accessing professional help as perceived by adolescents with anxiety/depressive disorders identified in the community. Twenty-two adolescents, aged 11-17 years, who met diagnostic criteria for a current anxiety and/or depressive disorder were identified through school-based screening. In-depth qualitative interviews were conducted one-to-one with each adolescent and adolescents' parents were interviewed separately for the purpose of data triangulation. Data were analysed using reflexive thematic analysis. We identified four themes capturing adolescent perceived barriers and facilitators to seeking/accessing professional help for anxiety and depressive disorders: (1) making sense of difficulties, (2) problem disclosure, (3) ambivalence to seeking help, and (4) the instrumental role of others. Barriers/facilitators identified within each theme reflect important developmental characteristics of adolescence, such as a growing need for autonomy and concerns around negative social evaluation. At the same time, the results highlight adolescents' dependency on other people, mainly their parents and school staff, when it comes to successfully accessing professional help for their mental health difficulties. This study identifies a number of barriers/facilitators that influence help-seeking behaviour of adolescents with anxiety and/or depressive disorders. These factors need to be addressed when targeting treatment utilisation rates in this particular group of young people.

Annual Research Review: Immersive virtual reality and digital applied gaming interventions for the treatment of mental health problems in children and young people: the need for rigorous treatment development and clinical evaluation.

BACKGROUND: Mental health problems in children and young people are common and can lead to poor long-term outcomes. Despite the availability of effective psychological interventions for mental health disorders, only a minority of affected children and young people access treatment. Digital interventions, such as applied games and virtual reality (VR), that target mental health problems in children and young people may hold a key to increasing access to, engagement with, and potentially the effectiveness of psychological treatments. To date, several applied games and VR interventions have been specifically developed for children and young people. This systematic review aims to identify and synthesize current data on the experience and effectiveness of applied games and VR for targeting mental health problems in children and young people (defined as average age of 18 years or below). METHODS: Electronic systematic searches were conducted in Medline, PsycINFO, CINAHL, and Web of Science. RESULTS: Nineteen studies were identified that examined nine applied games and two VR applications, and targeted symptoms of anxiety, depression, and phobias using both quantitative and qualitative methodologies. Existing evidence is at a very early stage and studies vary extensively in key methodological characteristics. For applied games, the most robust evidence is for adolescent depressive symptoms (medium clinical effect sizes). Insufficient research attention has been given to the efficacy of VR interventions in children and young people. CONCLUSIONS: The evidence to date is at a very early stage. Despite the enthusiasm for applied games and VR, existing interventions are limited in number and evidence of efficacy, and there is a clear need for further co-design, development, and evaluation of applied games and VR before they are routinely offered as treatments for children and young people with mental health problems.

Examining changes in parent-reported child and adolescent mental health throughout the UK's first COVID-19 national lockdown.

BACKGROUND: The COVID-19 pandemic has significantly changed the lives of children and adolescents, forcing them into periods of prolonged social isolation and time away from school. Understanding the psychological consequences of the UK's lockdown for children and adolescents, the associated risk factors, and how trajectories may vary for children and adolescents in different circumstances is essential so that the most vulnerable children and adolescents can be identified, and appropriate support can be implemented. METHODS: Participants were a convenience sample of parents and carers (n = 2,988) in the UK with children and adolescents aged between 4 and 16 years who completed an online survey about their child's mental health. Growth curve analysis was used to examine the changes in conduct problems, hyperactivity/inattention, and emotional symptoms between the end of March/beginning of April and July using data from monthly assessments over four months. Additionally, growth mixture modelling identified mental health trajectories for conduct problems, hyperactivity/inattention, and emotional symptoms separately, and subsequent regression models were used to estimate predictors of mental health trajectory membership. RESULTS: Overall levels of hyperactivity and conduct problems increased over time, whereas emotional symptoms remained relatively stable, though declined somewhat between June and July. Change over time varied according to child age, the presence of siblings, and with Special Educational Needs (SEN)/Neurodevelopmental Disorders (ND). Subsequent growth mixture modelling identified three, four, and five trajectories for hyperactivity/inattention, conduct problems, and emotional symptoms, respectively. Though many children maintained 'stable low' symptoms, others experienced elevated symptoms by July. These children were more likely to have a parent/carer with higher levels of psychological distress, to have SEN/ND, or to be younger in age. CONCLUSIONS: The findings support previous literature and highlight that certain risk factors were associated with poorer mental health trajectories for children and adolescents during the pandemic.

Why do children and adolescents (not) seek and access professional help for their mental health problems? A systematic review of quantitative and qualitative studies.

Mental health disorders in children and adolescents are highly prevalent yet undertreated. A detailed understanding of the reasons for not seeking or accessing help as perceived by young people is crucial to address this gap. We conducted a systematic review (PROSPERO 42018088591) of quantitative and qualitative studies reporting barriers and facilitators to children and adolescents seeking and accessing professional help for mental health problems. We identified 53 eligible studies; 22 provided quantitative data, 30 provided qualitative data, and one provided both. Four main barrier/facilitator themes were identified. Almost all studies (96%) reported barriers related to young people's individual factors, such as limited mental health knowledge and broader perceptions of help-seeking. The second most commonly (92%) reported theme related to social factors, for example, perceived social stigma and embarrassment. The third theme captured young people's perceptions of the therapeutic relationship with professionals (68%) including perceived confidentiality and the ability to trust an unknown person. The fourth theme related to systemic and structural barriers and facilitators (58%), such as financial costs associated with mental health services, logistical barriers, and the availability of professional help. The findings highlight the complex array of internal and external factors that determine whether young people seek and access help for mental health difficulties. In addition to making effective support more available, targeted evidence-based interventions are required to reduce perceived public stigma and improve young people's knowledge of mental health problems and available support, including what to expect from professionals and services.

Delivering cognitive therapy for adolescent social anxiety disorder in NHS CAMHS: a qualitative analysis of the experiences of young people, their parents and clinicians-in-training.

BACKGROUND: Social anxiety disorder (SAD) is common. It usually starts in adolescence, and without treatment can disrupt key developmental milestones. Existing generic treatments are less effective for young people with SAD than with other anxiety disorders, but an adaptation of an effective adult therapy (CT-SAD-A) has shown promising results for adolescents. AIMS: The aim of this study was to conduct a qualitative exploration to contribute towards the evaluation of CT-SAD-A for adoption into Child and Adolescent Mental Health Services (CAMHS). METHOD: We used interpretative phenomenological analysis (IPA) to analyse the transcripts of interviews with a sample of six young people, six parents and seven clinicians who were learning the treatment. RESULTS: Three cross-cutting themes were identified: (i) endorsing the treatment; (ii) finding therapy to be collaborative and active; challenging but helpful; and (iii) navigating change in a complex setting. Young people and parents found the treatment to be useful and acceptable, although simultaneously challenging. This was echoed by the clinicians, with particular reference to integrating CT-SAD-A within community CAMHS settings. CONCLUSIONS: The acceptability of the treatment with young people, their parents and clinicians suggests further work is warranted in order to support its development and implementation within CAMHS settings.

Delivering cognitive therapy for adolescent social anxiety disorder in NHS CAMHS: a clinical and cost analysis.

BACKGROUND: Cognitive therapy, based on the Clark and Wells (1995) model, is a first-line treatment for adults with social anxiety disorder (SAD), and findings from research settings suggest it has promise for use with adolescents (Cognitive Therapy for Social Anxiety Disorder in Adolescents; CT-SAD-A). However, for the treatment to be suitable for delivery in routine clinical care, two questions need to be addressed. AIMS: Can therapists be trained to achieve good outcomes in routine Child and Adolescent Mental Health Services (CAMHS), and what are the costs associated with training and treatment? METHOD: CAMHS therapists working in two NHS trusts received training in CT-SAD-A. They delivered the treatment to adolescents with SAD during a period of supervised practice. We examined the clinical outcomes for the 12 patients treated during this period, and estimated costs associated with treatment and training. RESULTS: Treatment produced significant improvements in social anxiety symptoms, general anxiety and depression symptoms, and reductions in putative process measures. Seventy-five per cent (9 out of 12) patients showed a reliable and clinically significant improvement in social anxiety symptoms, and 64% (7/11) lost their primary diagnosis of SAD. The total cost to the NHS of the CT-SAD-A treatment was £4047 (SD = £1003) per adolescent treated, of which £1861 (SD = £358) referred to the specific estimated cost of face-to-face delivery; the remaining cost was for training and supervising therapists who were not previously familiar with the treatment. CONCLUSIONS: This study provides preliminary evidence that clinicians can deliver good patient outcomes for adolescents with SAD in routine CAMHS during a period of supervised practice after receiving a 2-day training workshop. Furthermore, the cost of delivering CT-SAD-A with adolescents appeared to be no more than the cost of delivering CT-SAD with adults.

Practitioner Review: Anxiety disorders in children and young people - assessment and treatment.

Despite significant advancements in our knowledge of anxiety disorders in children and adolescents, they continue to be underrecognised and undertreated. It is critical that these disorders are taken seriously in children and young people as they are highly prevalent, have a negative impact on educational, social and health functioning, create a risk of ongoing anxiety and other mental health disorders across the life span and are associated with substantial economic burden. Yet very few children with anxiety disorders access evidence-based treatments, and there is an urgent need for widespread implementation of effective interventions. This review aimed to provide an overview of recent research developments that will be relevant to clinicians and policymakers, particularly focusing on the development and maintenance of child anxiety disorders and considerations for assessment and treatment. Given the critical need to increase access to effective support, we hope this review will contribute to driving forward a step change in treatment delivery for children and young people with anxiety disorders and their families.

The identification and psychological treatment of panic disorder in adolescents: a survey of CAMHS clinicians.

BACKGROUND: Panic disorder is experienced by around 1% of adolescents and has a significant impact on social and academic functioning. Preliminary evidence supports the effectiveness of panic disorder-specific treatment in adolescents with panic disorder; however, panic disorder may be overlooked in adolescents due to overlapping symptoms with other anxiety disorders and other difficulties being more noticeable to others. The aim of this study was to establish what training National Health Service (NHS) Child and Adolescent Mental Health Services (CAMHS) clinicians have received in psychological therapies and panic disorder and how they identify and treat panic disorder in adolescents. METHOD: CAMHS clinicians from a range of professions (n = 427), who were delivering psychological treatments to children and adolescents with anxiety disorders, participated. They completed a cross-sectional, online survey, including a vignette describing an adolescent with panic disorder, and were asked to identify the main diagnosis or presenting problem. RESULTS: Less than half the clinicians (48.6%) identified panic disorder or panic symptoms as the main presenting problem from the vignette. The majority of clinicians suggested CBT would be their treatment approach. However, few identified an evidence-based treatment protocol for working with young people with panic disorder. Almost half the sample had received no training in cognitive behaviour therapy (CBT), and around a fifth had received no training in delivering psychological treatments. CONCLUSIONS: Only half of CAMHS clinicians identified panic disorder from a vignette and although CBT treatments are widely offered, only a minority of adolescents with panic disorder are receiving treatments developed for and evaluated with young people with panic disorder. There is a vital need for clinician training, the use of tools that aid identification and the implementation of evidence-based treatments within CAMHS. KEY PRACTITIONER MESSAGE: Panic disorder affects around 1% of adolescents, adversely impacting social, academic and long-term life functioning. There is preliminary evidence for the effectiveness of a panic disorder-specific treatment of panic disorder in adolescents. Clinicians struggle to identify panic disorder or suitable treatment protocols for treating adolescents, although most would use CBT as the treatment approach. There is a vital need for clinician training, tools that aid identification of young people with panic disorder and evidence-based treatments that can be delivered in routine clinical settings.

Secondary school practitioners' beliefs about risk factors for school attendance problems: a qualitative study.

School staff have an important role to play in identifying and assisting pupils who require additional support to regularly attend school, but their beliefs about risk factors might influence their decisions regarding intervention. This qualitative study investigated educational practitioners' beliefs about risk factors for attendance problems. Sixteen practitioners from three secondary schools were interviewed via focus groups. Data were analysed using thematic analysis. Practitioners identified risk factors related to the individual, their family, peers and school. Poor mental health was identified as a risk factor, but practitioners primarily focused on anxiety rather than other mental health problems like depression or behavioural disorders. The overall perception was that school factors were less important than individual, family and peer factors. Implications include a need for increased awareness of the role of school factors in attendance problems, focus on promoting positive peer and pupil-teacher relationships, and collaborative working between young people, families and schools.

A randomized controlled trial of internet-delivered cognitive behaviour therapy for adolescent anxiety disorders in a routine clinical care setting with and without parent sessions.

BACKGROUND: Computerized treatments have been shown to be effective in young people with anxiety disorders within research settings. The aims of this study were to evaluate a self-completed, therapist-supported online treatment for adolescent anxiety disorders in a routine clinical care setting and examine whether additional sessions for parents improved treatment outcome. METHOD: Sixty adolescents (13-18 years) referred by primary and secondary care services for treatment of an anxiety disorder and their parent(s) were randomly allocated to begin treatment immediately or after a 16-week waitlist. Half the parents (receiving treatment immediately or after a waitlist) were allocated to receive sessions themselves. Assessments were conducted pre- and posttreatment and at 6-month follow-up. RESULTS: There was no significant difference posttreatment between the immediate treatment and waitlist groups in remission of primary anxiety disorder (Odds Ratio (OR) = 2.19, 95% CI: 0.72-6.70). Parent sessions did not significantly improve adolescent outcomes immediately or at 6-month follow-up (OR = 0.75, 95% CI: 0.26-2.15; OR = 1.14, 95% CI: 0.42-3.15). CONCLUSIONS: Within a routine clinical care setting, a therapist-supported online treatment failed to deliver significantly better outcomes for adolescents with anxiety disorders than a waitlist. Further research is needed to develop more effective treatments for this population.

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. © 2016 The Authors. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics Published by Wiley Periodicals, Inc.

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.

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.

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

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.