Editorial Perspective: Extending IPDMA methodology to drive treatment personalisation in child mental health.

To improve outcomes for youth who do not respond optimally to existing treatments, we need to identify robust predictors, moderators, and mediators that are ideal targets for personalisation in mental health care. We propose a solution to leverage the Individual Patient Data Meta-analysis (IPDMA) approach to allow broader access to individual-level data while maintaining methodological rigour. Such a resource has the potential to answer questions that are unable to be addressed by single studies, reduce researcher burden, and enable the application of newer statistical techniques, all to provide data-driven strategies for clinical decision-making. Using childhood anxiety as the worked example, the editorial perspective outlines the rationale for leveraging IPDMA methodology to build a data repository, the Platform for Anxiety Disorder Data in Youth. We also include recommendations to address the methods and challenges inherent in this endeavour.

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.

Interventions Targeting Negative Mental Imagery in Social Anxiety: A Systematic Review and Meta-Analysis of Characteristics and Outcomes.

Psychological treatment for social anxiety disorder (SAD) has been found to be less effective than for other anxiety disorders. Targeting the vivid and distressing negative mental images typically experienced by individuals with social anxiety could possibly enhance treatment effectiveness. To provide both clinicians and researchers with an overview of current applications, this systematic review and meta-analysis aimed to evaluate the possibilities and effects of imagery-based interventions that explicitly target negative images in (sub)clinical social anxiety. Based on a prespecified literature search, we included 21 studies, of which 12 studies included individuals with a clinical diagnosis of SAD. Imagery interventions (k = 28 intervention groups; only in adults) generally lasted one or two sessions and mostly used imagery rescripting with negative memories. Others used eye movement desensitization and reprocessing and imagery exposure with diverse intrusive images. Noncontrolled effects on social anxiety, imagery distress and imagery vividness were mostly large or medium. Meta-analyses with studies with control groups resulted in significant medium controlled effects on social anxiety (d = -0.50, k = 10) and imagery distress (d = -0.64, k = 8) and a nonsignificant effect on imagery vividness. Significant controlled effects were most evident in individuals with clinically diagnosed versus subclinical social anxiety. Overall, findings suggest promising effects of sessions targeting negative mental images. Limitations of the included studies and the analyses need to be considered. Future research should examine the addition to current SAD treatments and determine the relevance of specific imagery interventions. Studies involving children and adolescents are warranted.

Effectiveness of an add-on guided internet-based emotion regulation training (E-TRAIN) in adolescents with depressive and/or anxiety disorders: study protocol for a multicenter randomized controlled trial.

BACKGROUND: During adolescence, depressive and anxiety disorders are among the most common mental health disorders. Both disorders tend to persist, are predictive for other mental disorders, and are associated with severe impairment in diverse areas. Although Cognitive Behavioral Therapy (CBT) has proven to be an effective treatment, a considerable number of adolescents do not respond to CBT and residual symptoms often remain. Therefore, it is of great importance to improve treatment outcomes for depressed and/or anxious adolescents. Dysfunctional emotion regulation appears to be a transdiagnostic factor in the development and maintenance of aforementioned disorders. Enhancing emotion regulation skills may therefore reduce symptom severity. In light of this, we developed a guided internet-based emotion regulation training (E-TRAIN) that will be added to CBT. This study aims to evaluate the effectiveness of E-TRAIN + CBT compared to CBT alone on depressive and anxiety outcomes among adolescents with depressive and/or anxiety disorder. METHODS: In this multicenter two-arm randomized controlled trial with parallel group design, we aim to include 138 adolescents, aged 13-19 years, referred for treatment and diagnosed with depressive and/or anxiety disorder. Participants will be allocated to either CBT or CBT + E-TRAIN. Assessments will take place at baseline, and at 3 (T1), 6 (T2) and 12 (T3) months after baseline. We will conduct multi-informant assessments: the adolescent, a parent/caregiver, and the CBT therapist will be asked to fill in questionnaires. The continuous primary outcome measure is self-reported depressive and anxiety symptoms at six months after baseline, measured with the RCADS25. Secondary outcome measures include anxiety or depression diagnosis based on a semi-structured clinical interview, emotion (dys) regulation, and parent-report measures of anxiety, depression and emotion (dys) regulation. DISCUSSION: This study is the first randomized controlled trial to examine the additional value of a guided internet-based emotion regulation training to regular CBT in adolescents with depressive and/or anxiety disorders. If this intervention is effective, it can be implemented in mental health care and improve treatment for these young people. TRIAL REGISTRATION: Registered on June 23, 2021 in The Netherlands Trial Register (NL9564). Retrospectively registered. Recruitment started in May 2021 and is ongoing.

Youth Psychopathology in Daily Life: Systematically Reviewed Characteristics and Potentials of Ecological Momentary Assessment Applications.

Traditionally, symptoms of youth psychopathology are assessed with questionnaires, clinical interviews, or laboratory observations. Ecological Momentary Assessment (EMA) could be a particularly valuable additional methodology, since EMA enables examining the daily lives of youths near real-time, considering fluctuations and specific contexts of symptoms. This systematic review aimed to review the characteristics of current EMA applications and to provide a synthesis of their potential in studying youth psychopathology. Following a systematic search in PsycInfo and Medline, we identified 50 studies in clinical samples. Most studies used EMA to examine fluctuations in symptoms, affect, and behavior, and the relation with contextual factors. EMA was also used to investigate interactions between parents and their children over time, and to monitor and predict treatment response. EMA appeared feasible in youth and could provide valuable insights that contribute to understanding youth psychopathology. Benefits, gaps, and suggestions for future research and clinical practice are discussed.

Research Review: Recommendations for reporting on treatment trials for child and adolescent anxiety disorders - an international consensus statement.

BACKGROUND: Anxiety disorders in children and young people are common and bring significant personal and societal costs. Over the last two decades, there has been a substantial increase in research evaluating psychological and pharmacological treatments for anxiety disorders in children and young people and exciting and novel research has continued as the field strives to improve efficacy and effectiveness, and accessibility of interventions. This increase in research brings potential to draw together data across studies to compare treatment approaches and advance understanding of what works, how, and for whom. There are challenges to these efforts due largely to variation in studies' outcome measures and variation in the way study characteristics are reported, making it difficult to compare and/or combine studies, and this is likely to lead to faulty conclusions. Studies particularly vary in their reliance on child, parent, and/or assessor-based ratings across a range of outcomes, including remission of anxiety diagnosis, symptom reduction, and other domains of functioning (e.g., family relationships, peer relationships). METHODS: To address these challenges, we convened a series of international activities that brought together the views of key stakeholders (i.e., researchers, mental health professionals, young people, parents/caregivers) to develop recommendations for outcome measurement to be used in treatment trials for anxiety disorders in children and young people. RESULTS AND CONCLUSIONS: This article reports the results of these activities and offers recommendations for selection and reporting of outcome measures to (a) guide future research and (b) improve communication of what has been measured and reported. We offer these recommendations to promote international consistency in trial reporting and to enable the field to take full advantage of the great opportunities that come from data sharing going forward.

The Longitudinal Association Between Preadolescent Facial Emotion Identification and Family Factors, and Psychotic Experiences in Adolescence (The TRAILS Study).

The current study examines whether facial emotion identification and family factors at preadolescence (age 11) predict psychotic experiences 5 years later during adolescence (age 16) and whether family factors may mediate the association between facial emotion identification and psychotic experiences. Data was obtained from the epidemiological cohort TRAILS (N = 2059). At preadolescence, a facial emotion identification test and three questionnaires to assess family functioning, perceived parenting styles and parenting stress, were administered. At adolescence, a questionnaire on psychotic experiences was administered. Facial emotion identification at preadolescence was not associated with psychotic experiences at adolescence, and the mediational role of family functioning was not further explored. However, increased overprotective parenting at preadolescence was associated with a higher frequency of psychotic experiences and delusions at adolescence. Future research may examine the mechanism behind the role of overprotective parenting on psychotic experiences during adolescence.

Are parental changes related to improvements in preschool children's disruptive behaviours?

OBJECTIVE: To investigate whether changes in parenting after behavioural parent training in routine clinical care are associated with improvements in preschool children's disruptive behaviours. METHOD: We evaluated changes after parent training in maternal and paternal self-reports of parental discipline practices parenting sense of competence, and parents' ratings of child disruptive behaviours in parents of 63 children, with a one group pretest-posttest design. We also compared parenting parameters in this clinical sample with a nonclinical sample (n = 121). RESULTS: Mothers' self-reports of parental discipline practices and parenting sense of competence significantly improved after behavioural parent training. Less over-reactivity in both mothers and fathers was associated with fewer disruptive behaviours in children. After parent training, mothers' ratings of their discipline techniques did not differ anymore from those in the nonclinical sample. CONCLUSION: Positive changes in parental discipline practices, particularly less over-reactive parental behaviours, were related to a decrease of disruptive child behaviours.

Homesickness in social context: An ecological momentary assessment study among 1st-year university students.

Homesickness is common among university students and associated with mental health problems. Most previous studies assessed homesickness as a summary of the past weeks. However, there may be significant fluctuations across situations. At the current residence, homesickness may especially be triggered during (phone) interactions with attachment figures. Dutch and international 1st-year students (n = 92) completed the Utrecht Homesickness Scale and subsequently used a smartphone application to record social interactions for 14 days (ecological momentary assessment [EMA]). For each interaction they reported the social context (e.g. location, contact type) and their affective state, including homesickness. Homesickness in the past weeks and momentary homesickness were both higher in international students than in Dutch students. Feeling homesick was highest at participants' current residency, when interacting with parents, or when using video-chat. When participants felt more homesick, they reported less pleasant and more unpleasant affect. In conclusion, EMA provided insight in cross-situational variations in homesickness.

The development, validity, and reliability of the auditory vocal hallucination rating scale questionnaire (AVHRS-Q).

PURPOSE: The Auditory Vocal Hallucination Rating Scale Questionnaire (AVHRS-Q) is a short self-report measure assessing several characteristics of auditory vocal hallucinations (AVH) that was derived from a validated clinical interview (the auditory vocal hallucination rating scale; AVHRS). This study investigated the internal reliability, convergent validity, and divergent validity of the AVHRS-Q using two clinical samples. METHODS: In sample I, 32 psychiatric patients with AVH were recruited from an academic hospital service and assessed with the AVHRS and the AVHRS-Q. Data for sample II were retrospectively retrieved from a pseudonymised Routine Outcome Monitoring (ROM) database collected in the context of mental healthcare at the same academic hospital service. Data from 82 psychiatric patients with AVH were retrieved, who completed the AVHRS-Q, and measures of psychological distress (the Outcome Questionnaire; OQ-45, and the Symptom Checklist; SCL-90) and quality of life (the Manchester Short Assessment of Quality of Life; MANSA). RESULTS: The AVHRS-Q showed good internal consistency in both samples. Severity scores of the AVHRS-Q were strongly correlated to the severity scores of the AVHRS (r = 0.90, p < 0.01). The AVHRS-Q and AVHRS did not differ in the identification of mild and severe voice-hearers [X2 (1, N = 32) = 15.71]. AVHRS-Q severity scores had moderate correlations with measures of psychological distress (OQ-45, r = 0.43, p < 0.01; SCL-90, r = 0.50, p < 0.05) and quality of life (MANSA, r = - 0.22, p < 0.01). CONCLUSIONS: The AVHRS-Q demonstrated good reliability, convergent validity, and divergent validity, suggesting it can be applied in both clinical and research settings for a quick and reliable assessment of AVH.

Social skills group training in children with autism spectrum disorder: a randomized controlled trial.

In 122 high-functioning children with autism spectrum disorder (ASD; 9-13 years; 19 girls), we investigated the effectiveness of a 15-session social skills group training (SST) with and without parent and teacher involvement (PTI) in a randomized controlled trial with three conditions: SST (n = 47), SST-PTI (n = 51), and care-as-usual (CAU, n = 24). Hierarchical linear modeling was used for immediate and 6-month follow-up analyses. Measures were administered before randomization (blind), post-treatment and at follow-up (not blind). Trial registration: Dutch Trial Register; http://www.trialregister.nl ; NTR2405. At post-treatment, children in both SSTs had improved significantly more than CAU on the primary outcome, Vineland Socialization (SST: Cohen's d = 0.39; 95% CI - 2.23 to 3.11 and SST-PTI: d = 0.43; 95% CI - 2.19 to 3.15) and on the secondary outcome parent-SSRS "Cooperation" (SST: d = 0.43; 95% CI - 0.23 to 1.15 and SST-PTI: d = 0.45; 95% CI - 0.21 to 1.17), with no difference between post-treatment and follow-up. Additionally, children in SST-PTI improved significantly more on the teacher-SSRS than in CAU ["Cooperation" d =0.42 (95% CI - 0.33 to 1.13); "Assertion" d =0.34 (95% CI - 0.39 to 1.11); "Self-Control" d =0.61 (95% CI - 0.08 to 1.34)] and in SST ["Cooperation" d =0.34 (95% CI - 0.37 to 1.05); "Self-Control" d =0.59 (95% CI - 0.13 to 1.32)]. The current study corroborates earlier findings in smaller samples and wider age ranges, with small but statistically significant effects of SST for high-functioning pre-adolescent children with ASD. Parental and teacher involvement intensified treatment, yet did not yield an additional effect relative to SST for children only, as reported by parents. 6 months after training, no further improvement or decline was found.

The impact of treatment delivery format on response to cognitive behaviour therapy for preadolescent children with anxiety disorders.

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.

Exploring the relation between visual mental imagery and affect in the daily life of previously depressed and never depressed individuals.

Previously depressed individuals experience disturbances in affect. Affective disturbances may be related to visual mental imagery, given that imagery-based processing of emotional stimuli causes stronger affective responses than verbal processing in experimental laboratory studies. However, the role of imagery-based processing in everyday life is unknown. This study assessed mental imagery in the daily life of previously and never depressed individuals. Higher levels of visual mental imagery was hypothesised to be associated with more affective reactivity to both negatively and positively valenced mental representations. This study was the first to explore mental imagery in daily life using experience sampling methodology. Previously depressed (n = 10) and matched never depressed (n = 11) individuals participated in this study. Momentary affect and imagery-based processing were assessed using the "Imagine your mood" smartphone application. Participants recorded on average 136 momentary reports over a period of 8 weeks. The expected association between visual mental imagery and affective reactivity was not found. Unexpectedly, in both previously and never depressed individuals, higher levels of imagery-based processing of mental representations in daily life were significantly associated with better momentary mood and more positive affect, regardless of valence. The causality of effects remains to be examined in future studies.

Preschool children's response to behavioural parent training and parental predictors of outcome in routine clinical care.

OBJECTIVE: To investigate the effectiveness of behavioral parent training (BPT) for preschool children with disruptive behaviours and to explore parental predictors of response. METHODS: Parents of 68 preschool children, aged between 2.7 and 5.9 years, participated in BPT. We evaluated the changes in children's behaviour after BPT with a one group pretest-posttest design, using a waiting period for a double pretest. Outcome was based on parents' reports of the intensity and number of behaviour problems on the Eyberg Child Behavior Inventory. Predictor variables included parents' attention-deficit/hyperactivity disorder symptoms, antisocial behaviours, and alcohol use, and maternal parenting self-efficacy and disciplining. RESULTS: Mother-reported child behaviour problems did not change in the waiting period but improved significantly after BPT (d = 0.63). High levels of alcohol use by fathers and low levels of maternal ineffective disciplining were each associated with somewhat worse outcome. CONCLUSIONS: BPT under routine care conditions clearly improves disruptive behaviours in preschool children. Mothers who consider themselves as inadequate in disciplining and mothers whose partners do not consume high levels of alcohol report the largest improvements.

Predictors of discrepancies between fathers and mothers in rating behaviors of preschool children with and without ADHD.

To examine child factors and parental characteristics as predictors of discrepancies between parents' ratings of externalizing and internalizing behavior problems in a sample of preschool children with ADHD and behavior problems and in a nonclinical sample. We investigated correspondence and discrepancies between parents' ratings on the externalizing and internalizing behavior problems broadband scales of the Child Behavior Checklist version for preschool children (CBCL/1.5-5). Parents of 152 preschool children, with ADHD and behavior problems (n = 72) and nonclinical children (n = 80), aged between 28 and 72 months (M = 47.26, SD = 12.7), completed the CBCL/1.5-5. Candidate predictors of discrepancy included the child's age and sex, and parents' levels of parenting stress, depressive mood, attention-deficit and disruptive behavior. Hierarchical multiple regression analyses were conducted. Correspondence between parents, both for ratings on internalizing and externalizing behavior problems, was high (r = .63-.77). In the clinical sample, mothers rated the severity of externalizing behavior problems significantly higher than did fathers (p = < .001). Discrepancy between fathers and mothers on externalizing behavior problems was not predicted by child factors or interparental differences in psychopathology, but it was predicted by interparental differences in parenting stress (R 2 = .25, p < .001). This effect was significantly larger in the nonclinical sample (ΔR 2 = .06, p < .001). When parents disagree on the severity level of preschool children's externalizing behavior problems, the clinician should take into consideration that differences in parenting stress might be involved.

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.

A Genome-Wide Test of the Differential Susceptibility Hypothesis Reveals a Genetic Predictor of Differential Response to Psychological Treatments for Child Anxiety Disorders.

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.

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.