Eva Serlachius

While medication for attention deficit hyperactivity disorder (ADHD) is effective, predictors of treatment response remain poorly understood. Given the use of polygenic scores (PGS) in psychiatric conditions, we investigate their potential to predict ADHD medication response. In this work, we recruited 309 participants aged 6-17 years from the Swedish ADHD medication and predictors of treatment outcome (ADAPT) study (ClinicalTrials.gov: NCT02136147 ; June 2015), and calculated their PGS. Compared with a reference cohort (N=780), ADAPT showed higher PGS for ADHD (p<2.22e-16), and lower PGS for autism (p=0.0051), educational attainment (EA) (p=8e-10), and intelligence (p=7e-08). To assess the association between genetic effects and changes in Swanson, Nolan, and Pelham ADHD Rating Scale-version IV (SNAP-IV) scores, linear mixed-effects models tested the interaction between each PGS and time (baseline, 3-months). PGS for ADHD was associated with higher SNAP-IV scores overall (β=0.1419, p=0.0078, FDR=0.0293) but not with a change at follow-up; whereas, PGS for EA was associated with lower overall scores (β=-0.1161, p=0.0256, FDR=0.0679) and smaller reductions at follow-up (β=0.0946, p=0.0453, FDR=0.1130). Subgroup analyses indicated that these effects were more prominent in adolescents (≥13 years) and individuals classified as responders to treatment. We further explored machine learning models combining clinical and genetic information across 14 models with 49 features. Although models could not empirically generalize, estimated information-theoretic upper bounds for classification accuracy were 72% with PGS, 84% with clinical and demographic variables, and 92% when combined. This study highlights the potential of using PGS and combining genetic and clinical data to improve treatment stratification in ADHD.

Objectives: Trauma-focused cognitive behavioural therapy (TF-CBT) is the established first-line treatment for paediatric posttraumatic stress disorder (PTSD), but access to evidence-based care remains limited. This study aimed to evaluate the feasibility and acceptability of a therapist-guided, 12-week, internet-delivered TF-CBT (iTF-CBT) programme for adolescents with PTSD, and to explore preliminary changes in PTSD symptoms. Design: Single-group feasibility trial. Setting: Save the Children, Sweden. Participants: Twenty-two adolescents (13–17 years, 82% female) with primary PTSD. Interventions: A 12-week, therapist-guided, internet-delivered TF-CBT comprising eight modules and parallel caregiver modules with joint child–caregiver activities. Outcomes: Feasibility measures included recruitment pace, participant retention, treatment adherence (module completion), and therapist time. Acceptability was evaluated through satisfaction, credibility, negative effects, and reported adverse events. Preliminary treatment effects were evaluated as within-group changes in PTSD severity using independent evaluator-rated Clinician-Administered PTSD Scale (CAPS-CA-5) and the self-reported Child and Adolescent Trauma Screen 2 (CATS-2). Assessments occurred at baseline, during treatment, post-treatment, and at 1-month follow-up (primary endpoint). Results: Recruitment was completed after seven months of active enrolment. Retention and adherence were high, satisfaction and credibility ratings were favourable, and no intervention-related serious adverse events occurred. Clinically meaningful within-group improvements were observed at the primary endpoint, with large reductions on CAPS-CA-5 (Cohen’s d = 1.27) and CATS-2 (Cohen’s d = 1.51). Conclusions: Therapist-guided iTF-CBT for adolescents with PTSD was safe, feasible, acceptable, and associated with clinically meaningful symptom improvements. These findings support further evaluation in larger, controlled trials to determine efficacy, cost-effectiveness, and long-term outcomes. Trial registration: ClinicalTrials.gov NCT06185244 . Article Summary: Strengths and limitations of this study: First internet-delivered TF-CBT trial for young people with PTSD Use of clinician-rated PTSD symptoms (CAPS-CA-5) in combination with validated self-report measures. The intervention was developed in close collaboration with clinicians, alongside contributions from young people. Absence of a control group.

Excessive worry is common during adolescence and across psychiatric disorders. This study investigates whether: (1) internet-delivered cognitive behavioral therapy (ICBT) focused on exposure to uncertainty is effective in reducing excessive worry; (2) improvements in worry are associated with reductions in other psychiatric symptoms; and (3) changes in intolerance of uncertainty (IU) mediate worry outcomes. Adolescents (N = 62; aged 13-17 years) with excessive worry (≥30 total score on Penn State Worry Questionnaire for Children) were randomly allocated to 8 weeks of ICBT (n = 31) or a waitlist for ICBT (Waitlist, n = 31). Self-reported worry (primary outcome) was measured weekly for 12 weeks and controlled effects assessed at week 12 post-baseline. IU and a comparator mediator (depression) were measured every other week for 12 weeks during the treatment/waitlist phase. ICBT yielded significantly large reductions in worry compared to Waitlist (bootstrapped d = 0.59). Worry reductions mediated improvements in anxiety and depression symptoms. Changes in depression, but not IU, mediated worry outcomes. A brief course of worry-focused ICBT yielded moderate reductions in worry that was associated with improvements in anxiety and depression. Contrary to expectation, changes in IU did not explain worry reductions in this uncertainty- focused treatment. Further studies are needed to identify potential change mechanisms.

Predictors for the pharmacological effect of ADHD medication in children and adolescents are lacking. This study examined clinically relevant factors in a large (N = 638) prospective cohort reflecting real-world evidence. Children and adolescents aged 6–17 diagnosed with ADHD were evaluated at baseline and three months following ADHD medication initiation. The outcome was measured as a reduction in total SNAP-IV (Swanson Nolan and Pelham teacher and parent rating scale) score at three months compared to baseline. Outcome groups were defined as Responders (≥ 40% reduction), Intermediate Responders (≥ 20 to < 40% reduction), and Non-responders (< 20% reduction). Included independent variables were the Autism Spectrum Questionnaire (ASSQ), the Spence Children’s Anxiety Scale (SCAS), the Pediatric Side Effect Checklist (P-SEC), anthropometrics measures, geographical region, relative age, Children´s Global Assessment Scale (CGAS), Intelligence quotient (IQ), pharmacological treatment initiation month, ADHD symptom severity, ADHD presentation, and psychotic-like experiences. Multinomial logistic regression suggested that ADHD symptom severity, region, relative age, and stating ADHD medication at three-month follow-up were associated with the response outcome group. However, when validating the data with Bootstrap Forest, none of the variables were significant. Thus, in our large naturalistic cohort, we could not identify any clinically relevant factors that reliably predict pharmacological treatment outcomes. Trial registration: NCT02136147.

Background: Behavioural therapy for tics is difficult to access, and little is known about its effectiveness when delivered online. Objective: To investigate the clinical and cost-effectiveness of an online-delivered, therapist- and parent-supported therapy for young people with tic disorders. Design: Single-blind, parallel-group, randomised controlled trial, with 3-month (primary end point) and 6-month post-randomisation follow-up. Participants were individually randomised (1 : 1), using on online system, with block randomisations, stratified by site. Naturalistic follow-up was conducted at 12 and 18 months post-randomisation when participants were free to access non-trial interventions. A subset of participants participated in a process evaluation. Setting: Two hospitals (London and Nottingham) in England also accepting referrals from patient identification centres and online self-referrals. Participants: Children aged 9–17 years (1) with Tourette syndrome or chronic tic disorder, (2) with a Yale Global Tic Severity Scale-total tic severity score of 15 or more (or > 10 with only motor or vocal tics) and (3) having not received behavioural therapy for tics in the past 12 months or started/stopped medication for tics within the past 2 months. Interventions: Either 10 weeks of online, remotely delivered, therapist-supported exposure and response prevention therapy (intervention group) or online psychoeducation (control). Outcome: Primary outcome: Yale Global Tic Severity Scale-total tic severity score 3 months post-randomisation; analysis done in all randomised patients for whom data were available. Secondary outcomes included low mood, anxiety, treatment satisfaction and health resource use. Quality-adjusted life-years are derived from parent-completed quality-of-life measures. All trial staff, statisticians and the chief investigator were masked to group allocation. Results: Two hundred and twenty-four participants were randomised to the intervention (n = 112) or control (n = 112) group. Participants were mostly male (n = 177; 79%), with a mean age of 12 years. At 3 months the estimated mean difference in Yale Global Tic Severity Scale-total tic severity score between the groups adjusted for baseline and site was −2.29 points (95% confidence interval −3.86 to −0.71) in favour of therapy (effect size −0.31, 95% confidence interval −0.52 to −0.10). This effect was sustained throughout to the final follow-up at 18 months (−2.01 points, 95% confidence interval −3.86 to −0.15; effect size −0.27, 95% confidence interval −0.52 to −0.02). At 18 months the mean incremental cost per participant of the intervention compared to the control was £662 (95% confidence interval −£59 to £1384), with a mean incremental quality-adjusted life-year of 0.040 (95% confidence interval −0.004 to 0.083) per participant. The mean incremental cost per quality-adjusted life-year gained was £16,708. The intervention was acceptable and delivered with high fidelity. Parental engagement predicted child engagement and more positive clinical outcomes. Harms: Two serious, unrelated adverse events occurred in the control group. Limitations: We cannot separate the effects of digital online delivery and the therapy itself. The sample was predominately white and British, limiting generalisability. The design did not compare to face-to-face services. Conclusion: Online, therapist-supported behavioural therapy for young people with tic disorders is clinically and cost-effective in reducing tics, with durable benefits extending up to 18 months. Future work: Future work should compare online to face-to-face therapy and explore how to embed the intervention in clinical practice. Trial registration: This trial is registered as ISRCTN70758207; ClinicalTrials.gov (NCT03483493). The trial is now complete. Funding: This project was funded by the National Institute for Health and Care Research (NIHR) Health and Technology Assessment programme (project number 16/19/02) and will be published in full in Health and Technology Assessment; Vol. 27, No. 18. See the NIHR Journals Library website for further project information.

Approximately one-fifth of new parents struggle with unwanted intrusive thoughts (UITs) about intentionally harming their child. This study evaluated the initial efficacy, feasibility and acceptability of a novel online self-guided cognitive intervention for new parents with distressing UITs. Self-recruited parents (N = 43, 93% female, age 23-43 years) of children 0-3 years reporting daily distressing and impairing UITs were randomized to the 8-week self-guided online cognitive intervention or to waiting-list. The primary outcome was change on the Parental Thoughts and Behaviour Checklist (PTBC) from baseline to week 8 (post-intervention). The PTBC and negative appraisals (mediator) were assessed at baseline, weekly, post-intervention and at the 1-month follow-up. Results showed that the intervention led to statistically significant reductions in distress and impairment associated with UITs at post-intervention (controlled between-group d = 0.99, 95% CI 0.56 to 1.43), which were maintained at the 1-month follow-up (controlled between-group d = 0.90, 95% CI 0.41 to 1.39). The intervention was deemed to be feasible and acceptable by the participants. Change in negative appraisals mediated reductions in UITs but the model was sensitive to mediator-outcome confounders. We conclude that this novel online self-guided cognitive intervention can potentially reduce the distress and impairment associated with UITs in new parents. Large-scale trials are warranted.Abbreviations: UITs: Unwanted Intrusive Thoughts PTBC: Parental Thoughts and Behaviour Checklist.

Objective Access to effective treatments for adolescents with depression needs to improve. Few studies have evaluated behavioural activation (BA) for adolescent depression, and none remotely delivered BA. This study explored the feasibility and acceptability of therapist-guided and self-guided internet-delivered BA (I-BA) in preparation for a future randomised controlled trial (RCT). Design A single-blinded randomised controlled feasibility trial. Setting A specialist outpatient clinic in Sweden. Participants Thirty-two adolescents with mild-to-moderate major depression, aged 13–17 years. Interventions Ten weeks of therapist-guided I-BA or self-guided I-BA, or treatment as usual (TAU). Both versions of I-BA included parental support. TAU included referral to usual care within child and youth psychiatry or primary care. Outcomes Feasibility measures included study take-up, participant retention, acceptability, safety and satisfaction. The primary outcome measure was the blinded assessor-rated Children’s Depression Rating Scale, Revised. The primary endpoint was the 3-month follow-up. Results 154 adolescents were screened and 32 were randomised to therapist-guided I-BA (n=11), self-guided I-BA (n=10) or TAU (n=11). Participant retention was acceptable, with two drop-outs in TAU. Most participants in TAU had been offered interventions by the primary endpoint. The mean number of completed chapters (total of 8) for adolescents was 7.5 in therapist-guided I-BA and 5.4 in self-guided I-BA. No serious adverse events were recorded. Satisfaction was acceptable in both I-BA groups. Following an intent-to-treat approach, the linear mixed-effects model revealed that both therapist-guided and self-guided I-BA (Cohen’s d=2.43 and 2.23, respectively), but not TAU (Cohen’s d=0.95), showed statistically significant changes on the primary outcome measure with large within-group effect sizes. Conclusions Both therapist-guided and self-guided I-BA are acceptable and potentially efficacious treatments for adolescents with depression. It is feasible to conduct a large-scale RCT to establish the efficacy and cost-effectiveness of I-BA versus TAU. Trial registration number ClinicalTrials.gov Registry (NCT04117789).

Introduction: The operational definitions of treatment response, partial response, and remission in obsessive-compulsive disorder (OCD) are widely used in clinical trials and regular practice. However, the clinimetric sensitivity of these definitions, that is, whether they identify patients that experience meaningful changes in their everyday life, remains unexplored. Objective: The objective was to examine the clinimetric sensitivity of the operational definitions of treatment response, partial response, and remission in children and adults with OCD. Methods: Pre- and post-treatment data from five clinical trials and three cohort studies of children and adults with OCD (n = 1,528; 55.3% children, 61.1% female) were pooled. We compared (1) responders, partial responders, and non-responders and (2) remitters and non-remitters on self-reported OCD symptoms, clinician-rated general functioning, and self-reported quality of life. Remission was also evaluated against post-treatment diagnostic interviews. Results: Responders and remitters experienced large improvements across validators. Responders had greater improvements than partial responders and non-responders on self-reported OCD symptoms (Cohen’s d 0.65–1.13), clinician-rated functioning (Cohen’s d 0.53–1.03), and self-reported quality of life (Cohen’s d 0.63–0.73). Few meaningful differences emerged between partial responders and non-responders. Remitters had better outcomes across most validators than non-remitters. Remission criteria corresponded well with absence of post-treatment diagnosis (sensitivity/specificity: 93%/83%). Using both the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) and the Clinical Global Impression Scale yielded more conservative results and more robust changes across validators, compared to only using the Y-BOCS. Conclusions: The current definitions of treatment response and remission capture meaningful improvements in the everyday life of individuals with OCD, whereas the concept of partial response has dubious clinimetric sensitivity.