Gro Janne Wergeland

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

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

An effectiveness study of individual vs. group cognitive behavioral therapy for anxiety disorders in youth

OBJECTIVE Conducted a randomized controlled trial to investigate the effectiveness of cognitive behavioral therapy (CBT), and compared the relative effectiveness of individual (ICBT) and group (GCBT) treatment approaches for anxiety disorders in children and adolescents. METHODS Referred youth (N = 182, M age = 11.5 years, range 8-15 years, 53% girls) with separation anxiety, social phobia, or generalized anxiety disorder were randomly assigned to ICBT, GCBT or a waitlist control (WLC) in community clinics. Pre-, post-, and one year follow-up assessments included youth and parent completed diagnostic interview and symptom measures. After comparing CBT (ICBT and GCBT combined) to WLC, ICBT and GCBT were compared along diagnostic recovery rates, clinically significant improvement, and symptom measures scores using traditional hypothesis tests, as well as statistical equivalence tests. RESULTS Significantly more youth lost all anxiety disorders after CBT compared to WLC. Full diagnostic recovery rate was 25.3% for ICBT and 20.5% in GCBT, which was not significantly different. There was continued lack of significant differences between ICBT and GCBT at one year follow-up. However, equivalence between GCBT and ICBT could only be demonstrated for clinical severity rating of the principal anxiety disorder and child reported anxiety symptoms post-treatment. CONCLUSION Findings support the effectiveness of CBT compared to no intervention for youth with anxiety disorders, with no significant differences between ICBT and GCBT. However, the relatively low recovery rates highlight the need for further improvement of CBT programs and their transportability from university to community settings.

Cognitive behavioral and pharmacological treatments of OCD in children: A systematic review and meta-analysis

Obsessive-compulsive disorder (OCD) is ranked by the World Health Organization (WHO) among the 10 most debilitating disorders. The treatments which have been found effective are cognitive behavior therapy (CBT) and serotonin reuptake inhibitors (SRI). This meta-analysis includes all RCTs of CBT (25) and SRI (9) for OCD in youth using the Childrens Yale-Brown Obsessive Compulsive Scale (C-YBOCS). CBT yielded significantly lower attrition (12.7%) than SRI (23.5%) and placebo (24.7%). The effect sizes for comparisons of CBT with waiting-list (1.53), placebo (0.93), and SRI with placebo (0.51) were significant, whereas CBT vs. SRI (0.22) and Combo (CBT+SRI) vs. CBT (0.14) were not. Regarding response rate CBT (70%) and Combo (66%) were significantly higher than SRI (49%), which was higher than placebo (29%) and WLC (13%). As for remission CBT (53%) and Combo (49%) were significantly higher than SRI (24%), placebo (15%), and WLC (10%), which did not differ from each other. Combo was not more effective than CBT alone irrespective of initial severity of the samples. The randomized controlled trials (RCTs) have a number of methodological problems and recommendations for improving research methodology are discussed as well as clinical implications of the findings.

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.

Predictors of treatment outcome in an effectiveness trial of cognitive behavioral therapy for children with anxiety disorders

A substantial number of children with anxiety disorders do not improve following cognitive behavioral therapy (CBT). Recent effectiveness studies have found poorer outcome for CBT programs than what is typically found in efficacy studies. The present study examined predictors of treatment outcome among 181 children (aged 8-15 years), with separation anxiety, social phobia, or generalized anxiety disorder, who participated in a randomized, controlled effectiveness trial of a 10-session CBT program in community clinics. Potential predictors included baseline demographic, child, and parent factors. Outcomes were as follows: a) remission from all inclusion anxiety disorders; b) remission from the primary anxiety disorder; and c) child- and parent-rated reduction of anxiety symptoms at post-treatment and at 1-year follow-up. The most consistent findings across outcome measures and informants were that child-rated anxiety symptoms, functional impairment, a primary diagnosis of social phobia or separation anxiety disorder, and parent internalizing symptoms predicted poorer outcome at post-treatment. Child-rated anxiety symptoms, lower family social class, lower pretreatment child motivation, and parent internalizing symptoms predicted poorer outcome at 1-year follow-up. These results suggest that anxious children with more severe problems, and children of parents with elevated internalizing symptom levels, may be in need of modified, additional, or alternative interventions to achieve a positive treatment outcome.

Predictors of dropout from community clinic child CBT for anxiety disorders

The aim was to investigate predictors of treatment dropout among 182 children (aged 8-15 years) participating in an effectiveness trial of manual-based 10-session individual and group cognitive behavior therapy (CBT) for anxiety disorders in community clinics. The dropout rate was 14.4%, with no significant difference between the two treatment conditions. We examined predictors for overall dropout (n=26), early (≤session 4, n=15), and late dropout (≥session 5, n=11). Overall dropout was predicted by low child and parent rated treatment credibility, and high parent self-rated internalizing symptoms. Low child rated treatment credibility predicted both early and late dropout. High parent self-rated internalizing symptoms predicted early dropout, whereas low parent rated treatment credibility predicted late dropout. These results highlight the importance of addressing treatment credibility, and to offer support for parents with internalizing symptoms, to help children and families remain in treatment.

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

Background Anxiety disorders are common, and cognitive–behavioural therapy (CBT) is a first-line treatment. Candidate gene studies have suggested a genetic basis to treatment response, but findings have been inconsistent. Aims To perform the first genome-wide association study (GWAS) of psychological treatment response in children with anxiety disorders (n = 980). Method Presence and severity of anxiety was assessed using semi-structured interview at baseline, on completion of treatment (post-treatment), and 3 to 12 months after treatment completion (follow-up). DNA was genotyped using the Illumina Human Core Exome-12v1.0 array. Linear mixed models were used to test associations between genetic variants and response (change in symptom severity) immediately post-treatment and at 6-month follow-up. Results No variants passed a genome-wide significance threshold (P = 5 × 10−8) in either analysis. Four variants met criteria for suggestive significance (P<5 × 10−6) in association with response post-treatment, and three variants in the 6-month follow-up analysis. Conclusions This is the first genome-wide therapygenetic study. It suggests no common variants of very high effect underlie response to CBT. Future investigations should maximise power to detect single-variant and polygenic effects by using larger, more homogeneous cohorts.

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

Extinction learning is an important mechanism in the successful psychological treatment of anxiety. Individual differences in response and relapse following Cognitive Behavior Therapy may in part be explained by variability in the ease with which fears are extinguished or the vulnerability of these fears to re‐emerge. Given the role of the endocannabinoid system in fear extinction, this study investigates whether genetic variation in the endocannabinoid system explains individual differences in response to CBT. Children (N = 1,309) with a primary anxiety disorder diagnosis were recruited. We investigated the relationship between variation in the CNR1, CNR2, and FAAH genes and change in primary anxiety disorder severity between pre‐ and post‐treatment and during the follow‐up period in the full sample and a subset with fear‐based anxiety disorder diagnoses. Change in symptom severity during active treatment was nominally associated (P < 0.05) with two SNPs. During the follow‐up period, five SNPs were nominally associated with a poorer treatment response (rs806365 [CNR1]; rs2501431 [CNR2]; rs2070956 [CNR2]; rs7769940 [CNR1]; rs2209172 [FAAH]) and one with a more favorable response (rs6928813 [CNR1]). Within the fear‐based subset, the effect of rs806365 survived multiple testing corrections (P < 0.0016). We found very limited evidence for an association between variants in endocannabinoid system genes and treatment response once multiple testing corrections were applied. Larger, more homogenous cohorts are needed to allow the identification of variants of small but statistically significant effect and to estimate effect sizes for these variants with greater precision in order to determine their potential clinical utility.

Subtyping social anxiety in youth

Few empirical studies have examined subtypes of social anxiety disorder (SAD) in youth, and limited consensus resides on the nature of potential subtypes. Identifying subtypes, based on both fear and avoidance patterns, can help improve assessment and treatment of SAD. Subtypes of fear and avoidance were examined in a sample comprising 131 youth (age 8-15 years) diagnosed with SAD using the Anxiety Disorders Interview Schedule for children and parents (ADIS-C/P). Exploratory factor analysis of fear responses revealed three factors, defining fear subtypes linked to: (1) performance, (2) observation, and (3) interaction situations, respectively. Exploratory factor analysis of avoidance responses showed these were best represented by one avoidance factor. Few youth qualified exclusively for either of the fear subtypes, thus calling into question the clinical utility of these subtypes. Nevertheless, the findings indicate distinct contributions of fear and avoidance in SAD presentation. This finding might help clinicians target and improve treatment of the disorder.

Socio-Emotional Problems in Boys with Sex Chromosome Aneuploidies Compared to a Clinical Sample

Boys with sex chromosome aneuploidies (SCA) represent an understudied group. We examined parent-reported physical and socio-emotional problems in 25 boys with SCA (Mean age = 11.7 years, SD = 4.5). The majority had no severe physical health problems. One third of the sample had sleep problems and half of them had weekly or monthly pain. Total emotional and behavior problems, as assessed with the Strengths and Difficulties Questionnaire, were at the same level as reported for boys referred to child mental health clinics. Thus, boys with SCA may have the same need for psychological assessment and intervention as clinic-referred boys.