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Background: This study aimed to investigate the association between adolescents' adherence to attention-deficit/hyperactivity disorder (ADHD) medication and their risk of committing minor offenses., Methods: Using two Dutch databases, Statistics Netherlands (CBS) and the Foundation for Pharmaceutical Statistics (SFK), we aimed to investigate the association between adherence to ADHD medication and registered minor offenses between 2005 and 2019 of 18,234 adolescents (12-18 years). We used Cox regression analyses to compare the rate of committing minor offenses of adolescents during periods of high ADHD medication adherence compared to periods of low adherence (i.e., periods with or without sufficient amounts of dispensed medication). We additionally tested associations with adherence to selective serotonin reuptake inhibitors (SSRIs) as control medication and analyzed potential reverse causation., Results: High ADHD medication adherence was associated with a reduced risk of committing a minor offense of between 33% and 38% compared to low adherence periods of ≥3 months (hazard ratio [HR] 0.67, confidence interval [CI] 0.64-0.71) or ≥6 months (HR 0.62, CI 0.59-0.65). The reduction in risk can likely be attributed to ADHD medication, given the absence of effects of SSRIs and no reverse causation. The reduction rate remained between 16% and 55% per sex, stimulant versus non-stimulant medication, different offense categories and further sensitivity analyses., Conclusions: Among adolescents using ADHD medication, rates of criminality were lower during periods of high medication adherence, suggesting that adherence to ADHD medication may contribute to prevention of minor offenses in adolescents., (© 2024 The Authors. Journal of Child Psychology and Psychiatry published by John Wiley & Sons Ltd on behalf of Association for Child and Adolescent Mental Health.)

Subcortical brain structures are involved in developmental, psychiatric and neurological disorders. Here we performed genome-wide association studies meta-analyses of intracranial and nine subcortical brain volumes (brainstem, caudate nucleus, putamen, hippocampus, globus pallidus, thalamus, nucleus accumbens, amygdala and the ventral diencephalon) in 74,898 participants of European ancestry. We identified 254 independent loci associated with these brain volumes, explaining up to 35% of phenotypic variance. We observed gene expression in specific neural cell types across differentiation time points, including genes involved in intracellular signaling and brain aging-related processes. Polygenic scores for brain volumes showed predictive ability when applied to individuals of diverse ancestries. We observed causal genetic effects of brain volumes with Parkinson's disease and attention-deficit/hyperactivity disorder. Findings implicate specific gene expression patterns in brain development and genetic variants in comorbid neuropsychiatric disorders, which could point to a brain substrate and region of action for risk genes implicated in brain diseases., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Background: Economic evaluations of treatments for children with behavioural difficulties (i.e., characteristics of attention-deficit/hyperactivity disorder (ADHD) and/or oppositional defiant disorder (ODD)) usually rely on data of randomised controlled trials or are model-based. Findings of such studies may not be representative of cost-effectiveness and cost-utility in clinical practice. The current longitudinal study aimed to perform an economic evaluation of treatments for children with hyperactivity, impulsive behaviours, inattention, and/or behavioural difficulties using observational data that were obtained in clinical practice., Methods: Parents of 209 children (aged 5-12) who were referred to 1 of 10 Dutch youth mental healthcare institutions and who received treatment with (n = 108) or without (n = 101) the use of medication, filled out questionnaires at three timepoints (baseline, and ~ 6 and ~12 months later). Propensity score matching was used to make both groups comparable. Outcomes included quality-adjusted life years (QALYs), ADHD and ODD symptom severity, and impairment. Costs were measured from a societal perspective. Incremental cost-effectiveness ratios (ICERs) were estimated, and cost-effectiveness acceptability curves (CEACs) were derived to show uncertainty around the ICER., Results: Results did not show statistically significant differences in costs and effects between children who were treated with medication (alone or in combination with non-medication treatment) and those who were treated without medication. CEAC suggested that medication treatment has a 55% probability of being cost-effective at the €80,000 threshold and 36% at the €20,000 threshold compared with treatment without medication., Conclusions: Using observational data, our study did not provide clear evidence of the cost-effectiveness and cost-utility of treatment with medication compared with treatment without medication in clinical practice., (© 2024 The Author(s). Journal of Child Psychology and Psychiatry published by John Wiley & Sons Ltd on behalf of Association for Child and Adolescent Mental Health.)

The purpose of this study was to investigate whether face-to-face and therapist-assisted online (i.e., blended) behavioral parent training are effective on reducing disruptive behaviors in children with autism spectrum disorder (ASD) in routine mental health care. Ninety-seven children with ASD (4-13 years; 76 boys) were randomized to face-to-face parent training, blended parent training, or a waitlist control condition. We assessed treatment effects on parent-rated child noncompliance (primary outcome) and irritability (secondary outcome). This involved comparing both formats separately to the control condition using linear regression models. Child behaviors at 6 months follow-up were also examined. Children in the face-to-face parent training condition improved significantly more on noncompliance and irritability than children in the waitlist condition and improvements sustained to 6 months follow-up. Children in the blended condition did not improve more than children in the waitlist condition and attrition was high. Our results extend findings from efficacy studies to routine mental health care and advocate the use of face-to-face parent training for disruptive behaviors in children with ASD. More research into blended parent training programs for children with ASD and disruptive behaviors in routine mental health care should be conducted to draw more definite conclusions about the value of blended parent training for these children. Trial registration number NL4712; date of registration 22-10-2014., (© 2024. The Author(s).)

Background: Early detection of developmental problems is important as it allows for early intervention. Previous studies, in high-risk infants, found high predictive values of atypical scores on the Standardized Infant NeuroDevelopmental Assessment (SINDA) for later neurodevelopmental disorders (i.e., cerebral palsy, intellectual disability)., Aims: The present study explored SINDA's predictive values to identify risk of developmental delay at 4-5 years., Study Design: Cohort study., Subjects: 786 low-risk Dutch children (367 boys; median gestational age: 40 (27-42) weeks; mean birth weight: 3455 (SD 577) grams)., Outcome Measures: The SINDA was assessed at 2-12 months and risk of developmental delay was assessed using the Ages and Stages Questionnaire (ASQ) at 4-5 years. SINDA's predictive values were determined for five ASQ domains and the total ASQ score for children at risk of marked (all ASQ domains deviant) and any (one or more ASQ domains deviant) developmental delay., Results: Presence of one atypical SINDA scale score showed low to moderate sensitivities (12-88 %, depending on the SINDA scale and ASQ domain involved), moderate to high specificities (66-94 %), low positive predictive values (PPVs; 3-16 %), and high negative predictive values (NPVs; 95-100 %) for children at risk of marked and any developmental. Presence of multiple atypical SINDA scale scores predicted deviant ASQ domains slightly better (sensitivities = 11-62 %, specificities = 90-98 %, PPVs = 6-30 %, and NPVs = 95-100 %)., Conclusions: In low-risk infants, SINDA's predictive value is low for detecting children at risk of marked and any developmental delay at 4-5 years, as reflected by the low sensitivities. One of the explanations is the relatively low prevalence of developmental delay in low-risk populations. This might have consequences for the application of the SINDA in general healthcare settings (e.g. child health clinics), but further studies are needed to draw this conclusion., Competing Interests: Declaration of competing interest Mijna Hadders-Algra is one of the authors of the SINDA manual., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Only a small number of studies have assessed structural differences between the two hemispheres during childhood and adolescence. However, the existing findings lack consistency or are restricted to a particular brain region, a specific brain feature, or a relatively narrow age range. Here, we investigated associations between brain asymmetry and age as well as sex in one of the largest pediatric samples to date (n = 4265), aged 1-18 years, scanned at 69 sites participating in the ENIGMA (Enhancing NeuroImaging Genetics through Meta-Analysis) consortium. Our study revealed that significant brain asymmetries already exist in childhood, but their magnitude and direction depend on the brain region examined and the morphometric measurement used (cortical volume or thickness, regional surface area, or subcortical volume). With respect to effects of age, some asymmetries became weaker over time while others became stronger; sometimes they even reversed direction. With respect to sex differences, the total number of regions exhibiting significant asymmetries was larger in females than in males, while the total number of measurements indicating significant asymmetries was larger in males (as we obtained more than one measurement per cortical region). The magnitude of the significant asymmetries was also greater in males. However, effect sizes for both age effects and sex differences were small. Taken together, these findings suggest that cerebral asymmetries are an inherent organizational pattern of the brain that manifests early in life. Overall, brain asymmetry appears to be relatively stable throughout childhood and adolescence, with some differential effects in males and females., (© 2024 The Author(s). Human Brain Mapping published by Wiley Periodicals LLC.)

Objectives: Risperidone is commonly prescribed off-label in children and adolescents to manage disruptive behavior. This study aimed to investigate continued benefits of risperidone after at least 1 year of treatment and effects of discontinuation on physical health. Methods: Thirty-five youths (aged 6-18 years, intelligence quotient [IQ] >70) who were treated with risperidone for at least 1 year in regular clinical practice receiving outpatient care were randomly assigned to double-blind continuation of risperidone during 16 weeks or continuation for 2 weeks, gradual dose lowering over 6 weeks, and placebo for 8 weeks. Primary outcome was the total Disruptive Behavior (D-total) score of the parent-reported Nisonger Child Behavior Rating Form-Typical IQ (NCBRF-TIQ). Secondary outcome measures were the clinician-rated Clinical Global Impressions-Improvement scale (CGI-I), the parent, child, and teacher-rated Strengths and Difficulties Questionnaire (SDQ), the parent-rated Retrospective Modified Overt Aggression Scale (R-MOAS), and several health parameters (Udvalg for Kliniske Undersøgelser Side Effect Rating Scale [UKU-SERS], dyskinesia, akathisia, parkinsonism, body mass index (BMI), waist circumference, and laboratory outcomes). Mixed models for repeated measures were conducted for continuous outcomes and a chi-square test for the CGI-I. Results: Discontinuation of risperidone, as compared with continuation, was not associated with significant changes in parent-reported disruptive behaviors. However, discontinuation was related to significant deterioration in parent-rated verbal aggression, teacher-rated behavioral functioning, clinician-rated general functioning, and significant improvements in weight, BMI, waist circumference, and glucose, insulin, and prolactin levels. Although 56% of participants in the discontinuation group experienced relapse, causing premature withdrawal from the study, 44% was able to successfully discontinue risperidone. Conclusion: Discontinuation of risperidone was associated with deterioration on some, but not all behavioral measures according to this explorative study. Discontinuation was associated with important health gains. Despite long-term benefits of risperidone, attempts to withdraw risperidone should be undertaken in individual children. This is a crucial step in preventing harm and fostering health.

People with intellectual disabilities (IDs) often present with challenging behaviors (CBs) mostly due to inappropriate environments and mental and physical disorders. Integrative care is recommended to address CBs. However, in clinical practice, psychotropic drugs are often prescribed off-label for CBs, although the effectiveness is unclear, and side effects frequently occur. We conducted a cluster-randomized controlled study to investigate the effect of integrative care provided by a collaboration of an ID specialized mental healthcare team and participants' own ID service providers' care team on reducing CBs and inappropriate off-label psychotropic drug prescriptions compared with care as usual. Participants ( N = 33, aged 19-81 years) had a moderate, severe, or profound intellectual disability and used off-label psychotropic drugs. The primary outcome measures were the Aberrant Behavior Checklist and the total dose of psychotropic drug prescriptions. At the study endpoint of 40 weeks, we found no effect of the intervention on the total ABC score and on the total dose of psychotropic drug prescriptions. In the intervention group, however, the psychotropic drug dose decreased significantly, while CBs did not change. The small sample size and not-completed interventions due to organizational problems may have affected our findings. This study illustrates the difficulties in the implementation of integrative care.

Background: Tourette syndrome (TS) is a childhood-onset neurodevelopmental disorder of complex genetic architecture and is characterized by multiple motor tics and at least one vocal tic persisting for more than 1 year., Methods: We performed a genome-wide meta-analysis integrating a novel TS cohort with previously published data, resulting in a sample size of 6133 individuals with TS and 13,565 ancestry-matched control participants., Results: We identified a genome-wide significant locus on chromosome 5q15. Integration of expression quantitative trait locus, Hi-C (high-throughput chromosome conformation capture), and genome-wide association study data implicated the NR2F1 gene and associated long noncoding RNAs within the 5q15 locus. Heritability partitioning identified statistically significant enrichment in brain tissue histone marks, while polygenic risk scoring of brain volume data identified statistically significant associations with right and left thalamus volumes and right putamen volume., Conclusions: Our work presents novel insights into the neurobiology of TS, thereby opening up new directions for future studies., (Copyright © 2023 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

According to the World Health Organization (WHO), major depressive disorder (MDD) is the fourth leading cause of disability worldwide and the second most common disease after cardiovascular events. Approximately 280 million people live with MDD, with incidence varying by age and gender (female to male ratio of approximately 2:1). Although a variety of antidepressants are available for the different forms of MDD, there is still a high degree of individual variability in response and tolerability. Given the complexity and clinical heterogeneity of these disorders, a shift from "canonical treatment" to personalized medicine with improved patient stratification is needed. OPADE is a non-profit study that researches biomarkers in MDD to tailor personalized drug treatments, integrating genetics, epigenetics, microbiome, immune response, and clinical data for analysis. A total of 350 patients between 14 and 50 years will be recruited in 6 Countries (Italy, Colombia, Spain, The Netherlands, Turkey) for 24 months. Real-time electroencephalogram (EEG) and patient cognitive assessment will be correlated with biological sample analysis. A patient empowerment tool will be deployed to ensure patient commitment and to translate patient stories into data. The resulting data will be used to train the artificial intelligence/machine learning (AI/ML) predictive tool.

An Elimination Diet (ED) may be effective in reducing symptoms of Attention-Deficit/Hyperactivity Disorder (ADHD), but has never been compared to an active control condition [i.e., Healthy Diet (HD)]. In a two-armed RCT, a total of N = 165 children (5-12 years) with ADHD were randomized by means of minimization (1:1) to either an ED (N = 84) or HD (N = 81) within two Dutch child and adolescent psychiatry centers. The design included a non-randomized comparator arm including N = 58 children being treated with Care as Usual (CAU). Treatment allocation was unblinded. The primary outcome was a 5-point ordinal measure of respondership based on a combination of parent and teacher ratings on ADHD and emotion regulation, determined after 5 weeks of treatment. Ordinal regression analyses were done on an intention-to-treat basis. Fewer ED (35%) than HD (51%) participants showed a partial to full response, despite overall good-to-excellent treatment adherence (> 88%) and comparable high parental prior believes. A younger age and higher problem severity predicted a better respondership. CAU-preferring participants responded more often favorably (56%) compared to ED-but not HD-participants. Small-to-medium improvements in physical health (blood pressure, heart rate, and somatic complaints) were found in response to ED/HD versus decrements in response to CAU (74% received psychostimulants). The lack of superiority of the ED versus HD suggests that for the majority of children, dietary treatment response is not rooted in food-allergies/-sensitivities. The comparable results for treatment with HD and CAU are remarkable given that CAU participants were probably 'easier to treat' than HD (and ED) participants with proportionally fewer with a (suboptimal/non-response to) prior treatment with medication (4% versus 20%). Further assessment of long-term effects is needed to evaluate the potential place of dietary treatment within clinical guidelines. The trial is closed and registered in the Dutch trial registry, number NL5324 ( https://www.onderzoekmetmensen.nl/en/trial/25997 )., (© 2023. The Author(s).)

Tics can have a serious impact on the quality of life of children and their families. Behavioural therapy is an evidence-based first line treatment for tic disorders. This randomised controlled trial studied the efficacy of a brief, condensed group-based programme for children with tics (Dutch Trial Registry NL8052, 27 September 2019). Tackle your Tics is a four-day group treatment, including exposure and response prevention and supporting components, delivered by therapists and 'experts by experience'. We collected outcome measures at baseline (T1), directly post-treatment (T2), and at three- and 6-months follow-up (T3, T4) including tic severity (primary outcome measure), tic-related impairment, quality of life, tic-related cognitions, emotional/behavioural functioning, family functioning, treatment satisfaction and adherence. Outcomes directly post-treatment improved in both the treatment group (n = 52) and waiting list (n = 54), but showed no statistically significant differences between the conditions (differential change over time T1-T2) on tic severity (Yale Global Tic Severity Scale), quality of life (Gilles de la Tourette Syndrome Quality of Life Scale), tic-related cognitions and family functioning. At longer term (T3), again no between-group difference was found on tic severity, but tic-related impairment, quality of life and emotional/behavioural functioning significantly improved in the treatment group compared to the waiting list. Mean treatment satisfaction scores were favourable for both children and parents. Directly posttreatment, Tackle your Tics showed no superior effect compared to waiting list. However, on longer term this brief four-day group treatment was effective in improving tic-related impairment, quality of life and emotional/behavioural functioning., (© 2024. The Author(s).)

Background: The access to and uptake of evidence-based behavioral parent training for children with behavioral difficulties (i.e., oppositional, defiant, aggressive, hyperactive, impulsive, and inattentive behavior) are currently limited because of a scarcity of certified therapists and long waiting lists. These problems are in part due to the long and sometimes perceived as rigid nature of most evidence-based programs and result in few families starting behavioral parent training and high dropout rates. Brief and individually tailored parenting interventions may reduce these problems and make behavioral parent training more accessible. This protocol paper describes a two-arm, multi-center, randomized controlled trial on the short- and longer-term effectiveness and cost-effectiveness of a brief, individually tailored behavioral parent training program for children with behavioral difficulties., Methods: Parents of children aged 2-12 years referred to a child mental healthcare center are randomized to (i) three sessions of behavioral parent training with optional booster sessions or (ii) care as usual. To evaluate effectiveness, our primary outcome is the mean severity of five daily ratings by parents of four selected behavioral difficulties. Secondary outcomes include measures of parent and child behavior, well-being, and parent-child interaction. We explore whether child and parent characteristics moderate intervention effects. To evaluate cost-effectiveness, the use and costs of mental healthcare and utilities are measured. Finally, parents' and therapists' satisfaction with the brief program are explored. Measurements take place at baseline (T0), one week after the brief parent training, or eight weeks after baseline (in case of care as usual) (T1), and six months (T2) and twelve months (T3) after T1., Discussion: The results of this trial could have meaningful societal implications for children with behavioral difficulties and their parents. If we find the brief behavioral parent training to be more (cost-)effective than care as usual, it could be used in clinical practice to make parent training more accessible., Trial Registration: The trial is prospectively registered at ClinicalTrials.gov (NCT05591820) on October 24th, 2022 and updated throughout the trial., (© 2024. The Author(s).)

Psychopharmacological treatment is an important component of the multimodal intervention approach to treating mental health conditions in children and adolescents. Currently, there are many unmet needs but also opportunities, alongside possible risks to consider, regarding the pharmacological treatment of mental health conditions in children and adolescents. In this Position Paper, we highlight and address these unmet needs and opportunities, including the perspectives of clinicians and researchers from the European College of Neuropsychopharmacology-Child and Adolescent Network, alongside those of experts by lived experience from national and international associations, via a survey involving 644 participants from 13 countries, and of regulators, through representation from the European Medicines Agency. We present and discuss the evidence base for medications currently used for mental disorders in children and adolescents, medications in the pipeline, opportunities in the development of novel medications, crucial priorities for the conduct of future clinical studies, challenges and opportunities in terms of the regulatory and legislative framework, and innovations in the way research is conducted, reported, and promoted., Competing Interests: Declaration of interests SCo declares honoraria and reimbursement for travel and accommodation expenses for lectures from the following non-profit associations: Association for Child and Adolescent Central Health, Canadian ADHD Alliance Resource, British Association of Pharmacology (BAP), honorarium from Medice, and grants from NIHR, European Research Executive Agency, and Solent NHS Trust. DPO declares honoraria from Medice; and support for attending meetings or travel form Medice, Boehringer Ingelsheim, and HAC pharma. CA declares grants from Stanley Foundation, Brystol-Myers Squibb, Caja Navarra, Comunidad de Madrid, Fundación Alicia Kplopwitz, Fundación Familia Alonso, Foundacion Mutua Madrileña, Instituto de Salud Carlos III, NARSAD, and Ministerio Educacion; consulting fees from Acadia, AMGEN, Angelini, Astra Zeneca, Bristol-Myers Squibb, Fundación Alicia Koplowitz, Gedeon Richter, Instituto de Salud Carlos III, Janssen-Cilag, Lundbeck, Otsuka, Roche, Sage, Schering Plough, Shire, Ministerio Educación, Stanley Foundation, Sumitomo Dainippon Pharma, Sunovion, Takeda, and Teva; and honoraria from AMGEN, AstraZeneca, Bristol-Myers, Squibb, Exeltis, Janssen-Cilag Lundbeck, Otsuka, Sanofi, Takeda, Roche, Sumitomo, and Dainippon Pharma. IB reports honoraria, participation on a Data Safety Monitoring Board or Advisory Board, and payment for expert testimony from Angelini; and support for attending meetings from Angelini and Lundbeck. TB reports royalties from Hogrefe, Kohlhammer, CIP Medie, and Oxford University Press; honoraria from Janssen Cilag, Medice, and Takeda; participation on data safety monitoring for eye level, Infectopharm, Medice, Neurim Pharmaceuticals, Oberberg, GmbH, and Takeda. JKB reports consulting fees from Boehringer-Ingelheim and Servier; honoraria from Takeda and Medice; and participation on a Data Safety Monitoring Board or Advisory Board for Angelini. DCoghill reports grants from National Health and Medical Research Council (Institution), and Medical Research and Futures Fund (Institution); royalties from Oxford University Press and Cambridge University Press; honoraria from Takeda, Medice, Servier, and Novartis; support for attending meetings from European College of Neuropsychopharmacology; and unpaid leadership roles for Director of Australian ADHD Professionals Association and Director of European Network for Hyperkinetic Disorders. DCohen reports support from Agence Régionale de Santé d'Ile de France; grants from Janssen; honoraria form Otsuka; participation on a Data Safety Monitoring Board or Advisory Board for Lundbeck; and stocks with School Rebounds. CUC reports grants from Janssen and Teva; royalties from UpToDate; consulting fees from AbbVie, Acadia, Alkermes, Allergan, Angelini, Aristo, Boehringer-Ingelheim, Cardio Diagnostics, Cerevel, CNX Therapeutics, Compass Pathways, Darnitsa, Gedeon Richter, Hikma, Holmusk, IntraCellular Therapies, Janssen/J&J, Karuna, LB Pharma, Lundbeck, MedAvanteProPhase, MedInCell, Merck, Mindpax, Mitsubishi Tanabe Pharma, Mylan, Neurocrine, Newron, Noven, Otsuka, Pharmabrain, PPD Biotech, Recordati, Relmada, Reviva, Rovi, Seqirus, SK Life Science, Sunovion, Sun Pharma, Supernus, Takeda, Teva, and Viatris; payment for expert testimony from Janssen and Otsuka; participation on a Data Safety Monitoring for Lundbeck, Relmada, Reviva, Rovi, Supernus, and Teva; stock options from Cardio Diagnostics, Mindpax, LB Pharma, and Quantic. EG received support for attending meetings from European College of Neuropsychopharmacology 2023, CINP 2023, and World ADHD Congress 2023. PJH reports payment for educational material from Takeda. MP reports support from Janssen Cilag, Servier, Roche, Exeltis, Otsuka, Instituto de Salud Carlos III (Spanish Ministry of Health, now Spanish Ministry of Economy and Competitiveness), Horizon2020, EMA, CIBERSAM, Fundación Alicia Koplowitz, and Fundación Mutua Madrileña. PS reports grants from Anavex Life Sciences Corp, NIHR Invention for Innovation (i4i) Programme, MRC Clinical Academic Research Partnerships, NIHR HTA, NIHR EME, NIHR PGfAR, British Heart Foundation, Reverse Rett, Newron Pharmaceuticals, HealthTracker, and Anavex Scientific Corporation; royalties from HealthTracker; consulting fees from Anavex Scientific Corporation; honoraria from Egyptian Psychiatry Association; and stocks from HealthTracker. AS reports the following leadership roles: President ISRCAP; Chief Scientific Officer Mazi Gia to Paidi; Scientific Advisory Board MRC Adolescent Brain Development; and royalties from Oxford University Press and Cambridge University Press. BV reports grants from CRT Foundation, Italian Ministry of Research and Fondazione Italina Autismo; consulting fees from Medice and Ethos-Angelini; honoraria from Angelini and Menarini; support for attending meetings from Medice; participation in data safety monitoring from NIH and Alkermes. SW reports grants from EU H2022, Swiss National Foundation, WASAD Congress 2023, Heuberg Foundation, University Medical Center Groningen, Uniscientia Foundation, Swiss State Secretariat for Education, Research and Innovation, UZH Foundation and Erika Schwarz Foundation, Ebnet Foundation: Oxford Brain @McGill – ZNZ Partnership in the Neurosciences, European Cooperation in Science and Technology, Gertrud Thalmann Fonds of UPK Basel, Swiss National Foundation, Federal institute for Drugs and Medical Devices, Olga Mayenfisch Foundation; royalties from Georg Thieme Verlag KG Stuttgart, Hogrefe Publishing Group, Kohlhammer Publishing, Springer Berlin, Beltz publishing group; honoraria from Education Weiterbildungsverein Deutschschweizer Kliniken; Takeda Pharmaceuticals International leadership roles: President of the IPKJ Psychotherapy Institute, Board Member Schweizerischer Gesellschaft für Kinder- und Jugendpsychiatrie und Psychotherapie, Chair of ICOCS, Board Member ZNZ, SGZ. ICKW reports grants from Amgen, Janssen, GSK, Novartis, Pfizer, Bayer, Bristol-Myers Squibb, and Takeda, along with funding from the Hong Kong RGC and the Hong Kong Health and Medical Research Fund in Hong Kong, National Institute for Health Research in England, European Commission, National Health and Medical Research Council in Australia, and The European Union's Seventh Framework Programme for research, technological development, and demonstration. Consulting fees from IQVIA and WHO, payment for expert testimony from Court in Hong Kong; leadership roles: Member of Pharmacy and Poisons Board, Member of the Expert Committee on Clinical Events Assessment Following COVID-19 Immunization, and Member of the Advisory Panel on COVID-19 Vaccines of the Hong Kong Government. SCa reports leadership roles: Secretary of the Psychiatric section of SINPIA and Participation as investigator in sponsored clinical trials by Lundbeck, Otsuka, Janssen, Angelini, and Acadia. MB reports honoraria from Medice, Takeda, Martinsclub Bremen e.V., Das frühgeborene Kind e.V., APK e.V., Dreiländerinstitut, Senatsverwaltung Berlin, Lehrerakademie Dillingen, and leadership roles: ADHS Deutschland e.V. and Gamian Europe. NH reports leadership roles: ADHD Europe. KG reports grants from Johnson & Johnson Foundation, Boehringer Ingelheim, Janssen, Institute of Translation and Interpreting; support to attend meetings from European College of Neuropsychopharmacology; and participation on a Data Safety Monitoring Board or Advisory Board for Janssen and Boehringer Ingelheim. CM reports consulting fees from Janssen, Angelini, and Compass; honoraria from Angelini, Neuraxpharm, Lundbeck, Esteve, Pfizer, Sunovion, and British Association of Psychopharmacology; support for attending meetings or travel from Exeltis, Janssen, and BAP, participation on a Data Safety Monitoring Board or Advisory Board for Otsuka, Servier, and Nuvelution. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Impaired response inhibition is commonly present in individuals with attention-deficit/hyperactivity disorder (ADHD) and their unaffected relatives, suggesting impaired response inhibition as a candidate endophenotype in ADHD. Therefore, we explored whether behavioral and neural correlates of response inhibition are related to polygenic risk scores for ADHD (PRS-ADHD). We obtained functional magnetic resonance imaging of neural activity and behavioral measures during a stop-signal task in the NeuroIMAGE cohort, where inattention and hyperactivity-impulsivity symptoms were assessed with the Conners Parent Rating Scales. Our sample consisted of 178 ADHD cases, 103 unaffected siblings, and 173 controls (total N = 454; 8-29 years), for whom genome-wide genotyping was available. PRS-ADHD was constructed using the PRSice-2 software. We found PRS-ADHD to be associated with ADHD symptom severity, a slower and more variable response to Go-stimuli, and altered brain activation during response inhibition in several regions of the bilateral fronto-striatal network. Mean reaction time and intra-individual reaction time variability mediated the association of PRS-ADHD with ADHD symptoms (total, inattention, hyperactivity-impulsivity), and activity in the left temporal pole and anterior parahippocampal gyrus during failed inhibition mediated the relationship of PRS-ADHD with hyperactivity-impulsivity. Our findings indicate that PRS-ADHD are related to ADHD severity on a spectrum of clinical, sub-threshold, and normal levels; more importantly, we show a shared genetic etiology of ADHD and behavioral and neural correlates of response inhibition. Given the modest sample size of our study, future studies with higher power are warranted to explore mediation effects, suggesting that genetic liability to ADHD may adversely affect attention regulation on the behavioral level and point to a possible response inhibition-related mechanistic pathway from PRS-ADHD to hyperactivity-impulsivity., (© 2023. The Author(s).)

Background: Effects of staff provided positive behaviour support (PBS) for individuals with intellectual disabilities are unclear., Method: Using a multicentre non-randomised cluster controlled design, 26 teams of residential group homes, including 245 staff members of 167 individuals with intellectual disabilities, were allocated to a PBS or control group. Conducting multilevel analyses (n = 123) we examined individuals' changes in irritability, other challenging behaviours and quality of life., Results: Compared to controls, irritability did not significantly decrease more in the intervention group, but lethargic behaviours did. Personal development and self-determination significantly increased. Irritability of individuals in the PBS group with higher levels of irritability or lower levels of intellectual disability significantly reduced more compared to controls., Conclusions: PBS was effective in reducing irritability of individuals with severe levels of irritability or intellectual disabilities. Moreover, PBS decreased lethargic behaviours and improved several domains of quality of life., (© 2023 The Authors. Journal of Applied Research in Intellectual Disabilities published by John Wiley & Sons Ltd.)

Background: The COVID-19 pandemic negatively affected child and adolescent mental health and at the end of the pandemic (April 2022) child mental health had not returned to pre-pandemic levels. We investigated whether this observed increase in mental health problems has continued, halted, or reversed after the end of the pandemic in children from the general population and in children in psychiatric care., Methods: We collected parent-reported and child-reported data at two additional post-pandemic time points (November/December 2022 and March/April 2023) in children (8-18 years) from two general population samples ( N  = 818-1056 per measurement) and one clinical sample receiving psychiatric care ( N  = 320-370) and compared these with data from before the pandemic. We collected parent-reported data on internalizing and externalizing problems with the Brief Problem Monitor and self-reported data on Anxiety, Depressive symptoms, Sleep-related impairments, Anger, Global health, and Peer relations with the Patient-Reported Outcomes Measurement Information System (PROMIS ® )., Results: In the general population, parents reported no changes in externalizing problems but did report higher internalizing problems post-pandemic than pre-pandemic ( p  < 0.001). Children also reported increased mental health problems post-pandemic, especially in anxiety and depression, to a lesser extent in sleep-related impairment and global health, and least in anger (all p s < 0.01). In the clinical sample, parents reported higher internalizing ( p  < 0.001), but not externalizing problems post-pandemic compared to the start of the pandemic. Children reported greatest increases in problems in anxiety, depression, and global health, to a lesser extent on sleep-related impairment, and least on anger (all p s < 0.05)., Conclusions: Child mental health problems in the general population are substantially higher post-pandemic compared to pre-pandemic measurements. In children in psychiatric care mental health problems have increased during the pandemic and are substantially higher post-pandemic than at the start of the pandemic. Longitudinal and comparative studies are needed to assess what the most important drivers of these changes are., Competing Interests: MB is supported by a European Research Council consolidator Grant (WELL‐BEING 771057 PI Bartels). The authors have declared that they have no competing or potential conflicts of interest. All authors have seen and approved the manuscript., (© 2023 The Authors. JCPP Advances published by John Wiley & Sons Ltd on behalf of Association for Child and Adolescent Mental Health.)

Objectives: As part of the 'Suicidality: Treatment Occurring in Paediatrics (STOP)' study, we developed and performed psychometric validation of an electronic-clinical-outcome-assessment (eCOA), which included a patient-reported-outcome (ePRO), an observer-rated-outcome (eObsRO) for parents/carers and a clinician-reported-outcome (eClinRO) that allows identification and monitoring of medication-related suicidality (MRS) in adolescents., Design: STOP: Prospective study: A two phase validation study to assess the impact of medication on suicidal ideations., Setting: Six participating countries: Netherlands, UK, Germany, France, Spain and Italy that were part of the Community's Seventh Framework Programme (FP7/2007-2013) under grant agreement no. 261411., Participants: Cohort 1 consisted of 41 adolescent-completions, 50 parent-completions and 56 clinician-completions. Cohort 2 consisted of 244 adolescent-completions, 198 parent-completions and 240 clinician-completions from across the six countries. The scale was administered only to participants who have screened positive for the STOP-Suicidality Assessment Scale (STOP-SAS)., Results: A total of 24 items for the development of the STOP-Medication Suicidality Side Effects Scale (STOP-MS 3 ) were identified and three versions (for patients, parents and clinicians) of the STOP-MS 3 were developed and validated in two separate study cohorts comprising of adolescents, their parents and clinicians. Cronbach's α coefficients were above 0.85 for all domains. The inter-rater reliability of the STOP-MS 3 was good and significant for the adolescent (ePRO), clinician (eClinRO) (r=0.613), parent (eObsRO) versions of the scale (r=0.394) and parent and clinician (r=0.347). Exploratory factor analysis identified a 3-factor model across 24 items for the adolescent and parent version of the scale: (1) Emotional Dysregulation, (2) Somatic Dysregulation and (3) Behavioural Dysregulation. For the clinician version, a 4-factor model defined the scale structure: (1) Somatic Dysregulation, (2) Emotional Dysregulation, (3) Behavioural Dysregulation and (4) Mood Dysregulation., Conclusion: These findings suggest that the STOP-MS 3 scale, a web-based eCOA, allows identification and monitoring of MRS in the adolescent population and shows good reliability and validity., Competing Interests: Competing interests: PS is a co-inventor of the HealthTracker platform, a Chief Executive Officer (CEO) of HealthTracker Ltd and a shareholder of HealthTracker Ltd. and has received research funding for conducting clinical trials from Anavex Scientific Corp, GW Pharma, and Newron Pharmaceuticals. FF is a Chief Technology Officer (CTO) and shareholder of HealthTracker Ltd. KL was a Project Manager employed at HealthTracker Ltd. CA has been a consultant to or has received honoraria or grants from Acadia, Angelini, Gedeon Richter, Janssen Cilag, Lundbeck, Medscape, Minerva, Otsuka, Roche, Sage, Servier, Shire, Schering Plough, Sumitomo Dainippon Pharma, Sunovion and Takeda. JKB has been in the past 3 years a consultant to / member of advisory board of / and/or speaker for Takeda/Shire, Roche, Medice, Angelini, Janssen and Servier. He is not an employee of any of these companies, and not a stock shareholder of any of these companies. He has no other financial or material support, including expert testimony, patents, royalties. RWD has received compensation for serving as consultant or speaker, or he or the institution he works for have received research support or royalties from the organisations or companies indicated: EU (FP7 Programme), US National Institute of Mental Health (NIMH), German Federal Ministry of Health/Regulatory Agency (BMG/BfArM), German Federal Ministry of Education and Research (BMBF), German Research Foundation (DFG), Volkswagen Foundation; Boehringer Ingelheim, Ferring, Janssen-Cilag, Lilly, Lundbeck, Otsuka, Servier, Shire, Sunovion/Takeda and Theravance. He owns Eli Lilly stock. Since 2008, he has fully been affiliated with the Department of CAP, CIMH, Medical Faculty Mannheim, University of Heidelberg, Germany. DP-O reports that in the past 3 years, she had non-financial support from HAC Pharma and Boehringer-Ingelheim, honoraria from Medice outside the submitted work and unpaid scientific coordination for a study sponsored by Mensia. AZ in the past 3 years had been a consultant to / member of advisory board of / and/or speaker or received research grants from: Angelini, Jannsen, Lundbeck and Otsuka, Servier, Shire/Takeda. He is not an employee of any of these companies, and not a stock shareholder of any of these companies, He received royalties from Oxford University Press and Giuntio OS. RS has been an advisor to or has received honoraria from Takeda. US received speaker’s fees from Takeda/Shire. DC has been in the past 3 years a consultant to / member of advisory board of / and/or speaker for Takeda/Shire, Novartis, Medice and Servier. He has received royalties from Oxford University Press and Cambridge University Press. He is not an employee of any of these companies, and not a stock shareholder of any of these companies. Part of this data has been included in an FP7 STOP Report to the European Union., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Autism spectrum disorder (ASD), Tourette syndrome (TS), and attention-deficit/hyperactivity disorder (ADHD) display strong male sex bias, due to a combination of genetic and biological factors, as well as selective ascertainment. While the hemizygous nature of chromosome X (Chr X) in males has long been postulated as a key point of "male vulnerability", rare genetic variation on this chromosome has not been systematically characterized in large-scale whole exome sequencing studies of "idiopathic" ASD, TS, and ADHD. Here, we take advantage of informative recombinations in simplex ASD families to pinpoint risk-enriched regions on Chr X, within which rare maternally-inherited damaging variants carry substantial risk in males with ASD. We then apply a modified transmission disequilibrium test to 13,052 ASD probands and identify a novel high confidence ASD risk gene at exome-wide significance (MAGEC3). Finally, we observe that rare damaging variants within these risk regions carry similar effect sizes in males with TS or ADHD, further clarifying genetic mechanisms underlying male vulnerability in multiple neurodevelopmental disorders that can be exploited for systematic gene discovery., (© 2023. The Author(s).)

Youth with disruptive behavior showing high callous-unemotional (CU) traits and proactive aggression are often assumed to exhibit distinct impairments in emotion recognition from those showing mainly reactive aggression. Yet, reactive and proactive aggression and CU traits may co-occur to varying degrees across individuals. We aimed to investigate emotion recognition in more homogeneous clusters based on these three dimensions. In a sample of 243 youth (149 with disruptive behavior problems and 94 controls) aged 8-18 years, we used model-based clustering on self-report measures of CU traits and reactive and proactive aggression and compared the resulting clusters on emotion recognition (accuracy and response bias) and working memory. In addition to a Low and Low-Moderate symptom cluster, we identified two high CU clusters. The CU-Reactive cluster showed high reactive and low-to-medium proactive aggression; the CU-Mixed cluster showed high reactive and proactive aggression. Both CU clusters showed impaired fear recognition and working memory, whereas the CU-Reactive cluster also showed impaired recognition of disgust and sadness, partly explained by poor working memory, as well as a response bias for anger and happiness. Our results confirm the importance of CU traits as a core dimension along which youth with disruptive behavior may be characterized, yet challenge the view that high CU traits are closely linked to high proactive aggression per se. Notably, distinct neurocognitive processes may play a role in youth with high CU traits and reactive aggression with lower versus higher proactive aggression., (© 2022. The Author(s).)

The aim of the study was to assess internalizing problems before and during the pandemic with data from Dutch consortium Child and adolescent mental health and wellbeing in times of the COVID-19 pandemic, consisting of two Dutch general population samples (GS) and two clinical samples (CS) referred to youth/psychiatric care. Measures of internalizing problems were obtained from ongoing data collections pre-pandemic (N GS  = 35,357; N CS  = 4487) and twice during the pandemic, in Apr-May 2020 (N GS  = 3938; clinical: N CS  = 1008) and in Nov-Dec 2020 (N GS  = 1489; N CS  = 1536), in children and adolescents (8-18 years) with parent (Brief Problem Monitor) and/or child reports (Patient-Reported Outcomes Measurement Information System ® ). Results show that, in the general population, internalizing problems were higher during the first peak of the pandemic compared to pre-pandemic based on both child and parent reports. Yet, over the course of the pandemic, on both child and parent reports, similar or lower levels of internalizing problems were observed. Children in the clinical population reported more internalizing symptoms over the course of the pandemic while parents did not report differences in internalizing symptoms from pre-pandemic to the first peak of the pandemic nor over the course of the pandemic. Overall, the findings indicate that children and adolescents of both the general and clinical population were affected negatively by the pandemic in terms of their internalizing problems. Attention is therefore warranted to investigate long-term effects and to monitor if internalizing problems return to pre-pandemic levels or if they remain elevated post-pandemic., (© 2022. The Author(s).)

Background: Behavioural parent training is an evidence-based intervention for children with attention-deficit/hyperactivity disorder (ADHD), but little is known about the extent to which initial benefits are maintained., Aims: This meta-analytic review investigated longer-term (i.e., more than 2 months post-intervention) child and parental outcomes of behavioural parent training for children with ADHD., Materials & Methods: We searched for randomized controlled trials and examined ADHD symptoms, behavioural problems, positive parenting, negative parenting, parenting sense of competence, parent-child relationship quality, and parental mental health as outcomes. We included 27 studies (31 interventions; 217 effect sizes), used multilevel random-effects meta-analyses for between- and within-group comparisons (pre-intervention to follow-up and post-intervention to follow-up), and explored twelve predictors of change., Results: Between pre-intervention and follow-up ( M  = 5.3 months), we found significant small-to-moderate between-group effects of the intervention on ADHD symptoms, behavioural problems, positive parenting, parenting sense of competence and parent-child relationship quality. Within-group findings show sustained improvements in the intervention conditions for all outcome domains. There were few significant changes from post-intervention to follow-up. Additionally, the large majority of the individual effect sizes indicated sustained outcomes from post-intervention to follow-up. There were seven significant predictors of change in child outcomes, including stronger reductions in ADHD symptoms of girls and behaviour problems of younger children. In contrast with some meta-analyses on short-term effects, we found no differences between masked and unmasked outcomes on ADHD symptoms at follow-up., Discussion & Conclusion: We conclude that behavioural parent training has longer-term benefits for children's ADHD symptoms and behavioural problems, and for positive parenting behaviours, parenting sense of competence and quality of the parent-child relationship., Competing Interests: Prof. Dr. van der Oord has co‐developed a planning‐focused and solution‐focused treatment and other behavioural treatments, but has no financial interest in any of these. She has received research grants from ZonMw and the Research Foundation Flanders (FWO). She was an advisor of the Dutch ADHD guideline groups and is a member of a working group on ADHD of the Superior Health Council of Belgium. Dr. Luman has co‐developed a self‐help teacher training program, without financial interests. She has received research grants from ZonMw and was an advisor of the Dutch ADHD guideline groups. Prof. Dr. van den Hoofdakker has received royalties as one of the editors of “Sociaal Onhandig” (published by Van Gorcum), a Dutch book for parents that can be used in parent training. She has been involved in the development and evaluation of several parent and teacher training programs, without financial interests. She has been a member of Dutch ADHD guideline and practice standard groups. Dr. Dekkers, Dr. Hornstra, Dr. Leijten, Prof. Dr. Hoekstra, Dr. Groenman and Ms. Doffer have reported no biomedical financial interests or potential conflicts of interest., (© 2023 The Authors. JCPP Advances published by John Wiley & Sons Ltd on behalf of Association for Child and Adolescent Mental Health.)

Service providers may experience difficulties in providing appropriate care to optimize the functioning of individuals with intellectual disability and challenging behaviour. External consultation to identify and address the unmet support needs underlying the behaviour may be beneficial. Applying the multidimensional American Association Intellectual and Developmental Disabilities (AAIDD) model may facilitate this approach. We aimed to describe the content and outcomes of consultation for individuals with intellectual disability and challenging behaviour referred to the Dutch Centre for Consultation and Expertise in relation to the AAIDD model. Interventions were based on the clients' diagnostic, treatment, and support needs and were categorized according to the five dimensions of the AAIDD model. Outcomes of the consultations were assessed based on reports in the file and rated as 'clear improvement', 'improvement' or 'no improvement or deterioration'. In two-thirds of the 104 studied files, consultees were satisfied with the improvement in functioning. Interventions targeted the difficulties of the service providers in supporting their clients and were most often applied within the Health and Context dimensions of the AAIDD model. We may conclude that consultation of an expert team may be valuable to support the care providers, and the use of the AAIDD model may be helpful to address the unmet needs to improve the functioning of individuals with challenging behaviour.

Background: Chronic tic disorders (CTDs) commonly co-occur with other psychiatric disorders. CTDs have been linked to functional impairment and reduction in quality of life. Insufficient research is available on depressive symptoms in patients with CTD, especially children and adolescents, yielding conflicting findings. To investigate the presence of depressive symptoms in a cohort of children and young adolescents with CTD and to test whether they moderate the link between tic severity and functional impairment., Methods: The sample consisted of 85 children and adolescents (six to 18 years) with a CTD who were treated in a large referral center. Participants were evaluated using gold-standard self- and clinician-reporting instruments to measure tic symptom severity and tic-related functional impairment (Yale Global Tic Severity Scale), depression (Child Depression Inventory), and obsessive-compulsive symptoms (Children Yale Brown Obsessive Compulsive Scale)., Results: Depressive symptoms (mild to severe) were exhibited by 21% of our sample. Study participants with CTD and comorbid obsessive-compulsive disorder (OCD) and/or attention-deficit/hyperactivity disorder had higher rates of depressive symptoms compared with those without comorbidities. Significant correlations were found within and among all tic-related and OCD-related measures, yet depressive symptoms only correlated to tic-related functional impairment. Depression significantly and positively moderated the correlation between tic severity and tic-related functional impairment., Conclusions: Findings suggest that depression plays an important part as a moderator in the link between tic severity and functional impairment in children and adolescents. Our study highlights the importance of screening for and treating depression in patients with CTD., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Disruptive behavior disorders (DBD) are heterogeneous at the clinical and the biological level. Therefore, the aims were to dissect the heterogeneous neurodevelopmental deviations of the affective brain circuitry and provide an integration of these differences across modalities., Methods: We combined two novel approaches. First, normative modeling to map deviations from the typical age-related pattern at the level of the individual of (i) activity during emotion matching and (ii) of anatomical images derived from DBD cases ( n = 77) and controls ( n = 52) aged 8-18 years from the EU-funded Aggressotype and MATRICS consortia. Second, linked independent component analysis to integrate subject-specific deviations from both modalities., Results: While cases exhibited on average a higher activity than would be expected for their age during face processing in regions such as the amygdala when compared to controls these positive deviations were widespread at the individual level. A multimodal integration of all functional and anatomical deviations explained 23% of the variance in the clinical DBD phenotype. Most notably, the top marker, encompassing the default mode network (DMN) and subcortical regions such as the amygdala and the striatum, was related to aggression across the whole sample., Conclusions: Overall increased age-related deviations in the amygdala in DBD suggest a maturational delay, which has to be further validated in future studies. Further, the integration of individual deviation patterns from multiple imaging modalities allowed to dissect some of the heterogeneity of DBD and identified the DMN, the striatum and the amygdala as neural signatures that were associated with aggression.

Tourette syndrome (TS) is caused by multiple genetic and environmental factors. Yet, little is known about the interplay of these factors in the occurrence of tics. We investigated whether polygenic risk score (PRS) of TS and pregnancy-related factors together enhance the explained variance of tic occurrence in the Avon Longitudinal Study of Parents and Children (N cases  = 612; N controls  = 4,201; 50% male; mean age 13.8 years). We included a cumulative adverse pregnancy risk score, maternal anxiety and depression, and maternal smoking and alcohol use during pregnancy. We investigated possible joint effects of genetic and pregnancy-related risk factors using a multivariable approach, and explored mediation effects between the pregnancy-related risk factors in explaining tic presence. The PRS and the cumulative adverse pregnancy risk score, maternal anxiety, or maternal depression explained significantly more variance of tic presence compared to models including only the PRS. Furthermore, we found that the cumulative adverse pregnancy risk score mediated the association between several pregnancy-related factors (maternal anxiety, depression, and smoking) and tics. The combination of a PRS and pregnancy-related risk factors explained more variance of tics in a general population cohort compared to studying these factors in isolation., (© 2022 The Authors. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics published by Wiley Periodicals LLC.)

We aimed to identify promising novel medications for child and adolescent mental health problems. We systematically searched https://clinicaltrials.gov/ and https://www.clinicaltrialsregister.eu/ (from 01/01/2010-08/23/2022) for phase 2 or 3 randomized controlled trials (RCTs) of medications without regulatory approval in the US, Europe or Asia, including also RCTs of dietary interventions/probiotics. Additionally, we searched phase 4 RCTs of agents targeting unlicensed indications for children/adolescents with mental health disorders. We retrieved 234 ongoing or completed RCTs, including 26 (11%) with positive findings on ≥ 1 primary outcome, 43 (18%) with negative/unavailable results on every primary outcome, and 165 (70%) without publicly available statistical results. The only two compounds with evidence of significant effects that were replicated in ≥ 1 additional RCT without any negative RCTs were dasotraline for attention-deficit/hyperactivity disorder, and carbetocin for hyperphagia in Prader-Willi syndrome. Among other strategies, targeting specific symptom dimensions in samples stratified based on clinical characteristics or established biomarkers may increase chances of success in future development programmes., Competing Interests: Conflict of interest S Cortese declares honoraria and reimbursement for travel and accommodation expenses for lectures from the following non-profit associations: Association for Child and Adolescent Central Health (ACAMH), Canadian ADHD Alliance Resource (CADDRA), British Association of Pharmacology (BAP), and from Healthcare Convention for educational activity on ADHD. M Højlund has been a consultant to or has received honoraria from the Lundbeck Foundation, H. Lundbeck, and Otsuka. C Arango has been a consultant to or has received honoraria or grants from Acadia, Angelini, Biogen, Boehringer, Gedeon Richter, Janssen Cilag, Lundbeck, Medscape, Menarini, Minerva, Otsuka, Pfizer, Roche, Sage, Servier, Shire, Schering Plough, Sumitomo Dainippon Pharma, Sunovion and Takeda. I Baeza has received honoraria and travel support from Angelini, Otsuka-Lundbeck and Janssen. T Banaschewski served in an advisory or consultancy role for eye level, Infectopharm, Lundbeck, Medice, Neurim Pharmaceuticals, Oberberg GmbH, Roche, and Takeda. He received conference support or speaker’s fee by Janssen, Medice and Takeda. He received royalities from Hogrefe, Kohlhammer, CIP Medien, Oxford University Press; the present work is unrelated to these relationships. JK Buitelaar has been a consultant to / member of advisory board of / and/or speaker for Takeda, Medice, Angelini, Janssen, Boehringer-Ingelheim and Servier. He is not an employee of any of these companies, and not a stock shareholder of any of these companies. He has no other financial or material support, including expert testimony, patents, royalties. D Coghill served in an advisory or consultancy role for Medice, Novartis, Servier, and Shire/Takeda. He received conference support or speaker’s fee from Medice, Servier, and Shire/Takeda. He received royalties from Cambridge University Press and Oxford University Press; He is not an employee of any of these companies, and not a stock shareholder of any of these companies and the present work is unrelated to these relationships. D Cohen has been a consultant or has received honoraria from Janssen/J&J and Otsuka; he served on a Data Safety Monitoring Board for Lundbeck. CU Correll has been a consultant and/or advisor to or has received honoraria from: AbbVie, Acadia, Alkermes, Allergan, Angelini, Aristo, Boehringer-Ingelheim, Cardio Diagnostics, Cerevel, CNX Therapeutics, Compass Pathways, Darnitsa, Gedeon Richter, Hikma, Holmusk, IntraCellular Therapies, Janssen/J&J, Karuna, LB Pharma, Lundbeck, MedAvante-ProPhase, MedInCell, Merck, Mindpax, Mitsubishi Tanabe Pharma, Mylan, Neurocrine, Newron, Noven, Otsuka, Pharmabrain, PPD Biotech, Recordati, Relmada, Reviva, Rovi, Seqirus, SK Life Science, Sunovion, Sun Pharma, Supernus, Takeda, Teva, and Viatris. He provided expert testimony for Janssen and Otsuka. He served on a Data Safety Monitoring Board for Lundbeck, Relmada, Reviva, Rovi, Supernus, and Teva. He has received grant support from Janssen and Takeda. He received royalties from UpToDate and is also a stock option holder of Cardio Diagnostics, Mindpax, LB Pharma and Quantic. E Grunblatt received grant support from MEDICE Arzneimittel Pütter GmbH & Co KG. C Moreno has received honoraria as a consultant and/or advisor and/or for lectures from Angelini, Esteve, Exeltis, Janssen, Lundbeck, Neuraxpharm, Nuvelution, Otsuka, Pfizer, Servier and Sunovion outside the submitted work. M Parellada has been a consultant to or has received honoraria or grants from Angelini, Janssen Cilag, Exeltis, Lundbeck, Otsuka, Pfizer, Roche, Sage, Servier. A.M. Persico has been a consultant to and/or speaker for and has received honoraria from Servier, Sanofi, and Healx Limited. In the last 3 years, D. Purper-Ouakil reports honoraria/non-financial support from Medice and Shire/Takeda, non-financial support from HAC Pharma, and has worked as an unpaid scientific coordinator for Mensia, all outside the submitted work. In the last 2 years, B Vitiello was a paid consultant for Medice, Menarini, Angelini, and Alkermes Pharmaceuticals. ICKW reports research funding outside the submitted work from Amgen, Bristol Myers Squibb, Pfizer, Janssen, Bayer, GSK, Novartis, Takeda, the Hong Kong Research Grants Council, the Hong Kong Health and Medical Research Fund, the Hong Kong Innovation and Technology Commission, the NIHR, the European Commission, and the Australian National Health and Medical Research Council, and has also received expert testimony payment from the Hong Kong Court of Final Appeal in the previous 3 years and consultancy fee from IQVIA and World Health Organization. In the last 3 years, V Roessner received no honoraria from pharmaceutical companies. He received royalties from Hogrefe, Oxford University Press; the present work is unrelated to these relationships. The other authors have no conflicts of interest to declare., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Guideline adherence is important to ensure optimal and safe use of methylphenidate for children and adolescents with attention-deficit/hyperactivity disorder (ADHD). We investigated adherence to Dutch guidelines regarding dosing and monitoring of methylphenidate in child and adolescent mental health care and pediatric treatment settings. Methods: Five hundred six medical records of children and adolescents were investigated in 2015 and 2016. We assessed adherence to the following guideline recommendations: (1) at least four visits during the dose-finding phase; (2) monitoring thereafter at least every 6 months; (3) measuring height and weight at least annually; and (4) the use of validated questionnaires to assess treatment response. Pearson's chi-squared test statistics were used to examine differences between settings. Results: Only a small portion of patients had at least four visits during the dose-finding phase (5.1% in the first 4 weeks to 12.4% in the first 6 weeks). Also, less than half of the patients (48.4%) were seen at least every 6 months. Height was recorded at least annually in 42.0% of patients, weight in 44.9%, and both recorded in a growth chart in 19.5%. Questionnaires to assess treatment response were only used in 2.3% of all visits. When comparing both settings, more patients in the pediatric settings were seen every 6 months, although height and weight were recorded more often in the mental health care setting. Conclusion: Overall, guideline adherence was low. Training of clinicians and adding guideline recommendations to electronic medical records templates may improve adherence. Additionally, we should aim to close the gap between guidelines and clinical practice by looking critically at the feasibility of guidelines.

To ensure the continuity of care during the COVID-19 pandemic, clinicians in Child and Adolescent Psychiatry (CAP) were forced to immediately adapt in-person treatment into remote treatment. This study aimed to examine the effects of pre-COVID-19 training in- and use of telepsychiatry on CAP clinicians' impressions of telepsychiatry during the first two weeks of the Dutch COVID-19 related lockdown, providing a first insight into the preparations necessary for the implementation and provision of telepsychiatry during emergency situations. All clinicians employed by five specialized CAP centres across the Netherlands were invited to fill in a questionnaire that was specifically developed to study CAP clinicians' impressions of telepsychiatry during the COVID-19 pandemic. A total of 1065 clinicians gave informed consent and participated in the study. A significant association was found between pre-COVID-19 training and/or use of telepsychiatry and CAP clinicians' impressions of telepsychiatry. By far, the most favourable impressions were reported by participants that were both trained and made use of telepsychiatry before the pandemic. Participants with either training or use separately reported only slightly more favourable impressions than participants without any previous training or use. The expertise required to provide telepsychiatry is not one-and-the-same as the expertise that is honed through face-to-face consultation. The findings of this study strongly suggest that, separately, both training and (clinical) practice fail to sufficiently support CAP clinicians in the implementation and provision of telepsychiatry. It is therefore recommended that training and (clinical) practice are provided in conjunction., (© 2022. The Author(s).)

Some retrospective studies suggest that psychosocial stressors trigger the onset of tics. This study examined prospective hypothalamic-pituitary-adrenal (HPA) axis activity and perceived stress prior to tic onset. In the present study, 259 children at high risk for developing tics were assessed for hair cortisol concentration (HCC) and parent-on-child-reported perceived stress four-monthly over a three-year period. We used (i) generalised additive modelling (GAM) to investigate the time effects on HCC (hair samples n = 765) and perceived stress (questionnaires n = 1019) prior to tic onset and (ii) binary logistic regression to predict tic onset in a smaller subsample with at least three consecutive assessments (six to nine months before, two to five months before, and at tic onset). GAM results indicated a non-linear increasing course of HCC in children who developed tics, and a steady HCC course in those without tics, as well as a linear-increasing course of perceived stress in both groups. Logistic regression showed that with a higher HCC in hair samples collected in a range of two to five months before tic onset (which refers to cortisol exposure in a range of four to eight months), the relative likelihood of tic onset rose. Our study suggests increased stress prior to tic onset, as evidenced by higher HCC several months before tic onset.

Background: This metaregression analysis examined which behavioral techniques that are commonly used in behavioral parent and teacher training programs for children with attention-deficit/hyperactivity disorder (ADHD) were related to program effectiveness on children's behavioral outcomes., Methods: We included 32 randomized controlled trials (N = 2594 children) investigating behavioral parent training, teacher training, or a combination, in children with ADHD under 18 years. Outcomes were symptom counts of total ADHD, inattention, and hyperactivity-impulsivity and behavioral problems. The dosage of techniques was extracted from the intervention manuals. Metaregression was used to assess which techniques and intervention characteristics (setting, delivery method, duration, and home-school collaboration) were associated with intervention effectiveness., Results: Higher dosage of psycho-education for parents was associated with smaller effects on behavioral problems and, only in case of parent training, also with smaller effects on ADHD symptoms. Higher dosage of teaching parents/teachers to use negative consequences was associated with larger effects on behavioral problems. Individual training compared with group training was associated with larger effects on ADHD and hyperactivity-impulsivity symptoms., Conclusions: This study provides first insights into the specific techniques that are essential in behavioral parent and teacher training programs for children with ADHD. This knowledge can eventually be used to improve and tailor interventions., (© 2022 The Authors. Child and Adolescent Mental Health published by John Wiley & Sons Ltd on behalf of Association for Child and Adolescent Mental Health.)

Background: The COVID-19 pandemic has had an acute impact on child mental and social health, but long-term effects are still unclear. We examined how child mental health has developed since the start of the COVID-19 pandemic up to 2 years into the pandemic (April 2022)., Methods: We included children (age 8-18) from two general population samples ( N  = 222-1333 per measurement and N  = 2401-13,362 for pre-covid data) and one clinical sample receiving psychiatric care ( N  = 334-748). Behavioral questionnaire data were assessed five times from April 2020 till April 2022 and pre-pandemic data were available for both general population samples. We collected parent-reported data on internalizing and externalizing problems with the Brief Problem Monitor and self-reported data on Anxiety, Depressive symptoms, Sleep-related impairments, Anger, Global health, and Peer relations with the Patient-Reported Outcomes Measurement Information System (PROMIS®)., Results: In all samples, parents reported overall increased internalizing problems, but no increases in externalizing problems, in their children. Children from the general population self-reported increased mental health problems from before to during the pandemic on all six PROMIS domains, with generally worst scores in April 2021, and scores improving toward April 2022 but not to pre-pandemic norms. Children from the clinical sample reported increased mental health problems throughout the pandemic, with generally worst scores in April 2021 or April 2022 and no improvement. We found evidence of minor age effects and no sex effects., Conclusions: Child mental health in the general population has deteriorated during the first phase of the COVID-19 pandemic, has improved since April 2021, but has not yet returned to pre-pandemic levels. Children in psychiatric care show worsening of mental health problems during the pandemic, which has not improved since. Changes in child mental health should be monitored comprehensively to inform health care and policy., Competing Interests: MB is supported by a European Research Council consolidator Grant (WELL‐BEING 771057 PI Bartels). The authors have declared that they have no competing or potential conflicts of interest., (© 2023 The Authors. JCPP Advances published by John Wiley & Sons Ltd on behalf of Association for Child and Adolescent Mental Health.)

Background: Interventions for challenging behaviours in individuals with intellectual disabilities benefit from outcome monitoring that takes clients' preferences into account. We determined clients' and representatives' preferred outcome domains and measures to secure their involvement in treatment decisions for challenging behaviours., Method: We used an inclusive Delphi method. A focus group of individuals with mild intellectual disabilities and representatives of those with moderate and severe intellectual disabilities prepared the first round by assisting us in collecting possible outcomes. Panels of individuals with intellectual disabilities and representatives were composed to achieve consensus on instruments for preferred outcome domains., Results: Preferred outcome domains were behaviour, side-effects of psychotropic drugs, quality of life, daily functioning, caregiver burden and family quality of life. Corresponding outcome measures included self-report, interview and proxy-scales, including spoken versions., Conclusion: Including the preferred domains on outcomes of interventions for challenging behaviours is recommended. Research on corresponding outcome measures is necessary., (© 2022 John Wiley & Sons Ltd.)

An important question in mental healthcare for children is whether treatments are effective and safe in the long run. Here, we comment on a recent editorial perspective by Roest et al. (2022), who argue, based on an overview of systematic reviews, 'that there is no convincing evidence that interventions for the most common childhood disorders are beneficial in the long term'. We believe that the available evidence does not justify this conclusion and express our concern regarding the harmful effects of their message. We show that there is evidence to suggest beneficial longer term treatment effects for each of the disorders and explain why evidence-based treatment should be offered to children with mental disorders., (© 2022 The Authors. Journal of Child Psychology and Psychiatry published by John Wiley & Sons Ltd on behalf of Association for Child and Adolescent Mental Health.)

Tourette Syndrome (TS) is a complex neurodevelopmental disorder characterized by vocal and motor tics lasting more than a year. It is highly polygenic in nature with both rare and common previously associated variants. Epidemiological studies have shown TS to be correlated with other phenotypes, but large-scale phenome wide analyses in biobank level data have not been performed to date. In this study, we used the summary statistics from the latest meta-analysis of TS to calculate the polygenic risk score (PRS) of individuals in the UK Biobank data and applied a Phenome Wide Association Study (PheWAS) approach to determine the association of disease risk with a wide range of phenotypes. A total of 57 traits were found to be significantly associated with TS polygenic risk, including multiple psychosocial factors and mental health conditions such as anxiety disorder and depression. Additional associations were observed with complex non-psychiatric disorders such as Type 2 diabetes, heart palpitations, and respiratory conditions. Cross-disorder comparisons of phenotypic associations with genetic risk for other childhood-onset disorders (e.g.: attention deficit hyperactivity disorder [ADHD], autism spectrum disorder [ASD], and obsessive-compulsive disorder [OCD]) indicated an overlap in associations between TS and these disorders. ADHD and ASD had a similar direction of effect with TS while OCD had an opposite direction of effect for all traits except mental health factors. Sex-specific PheWAS analysis identified differences in the associations with TS genetic risk between males and females. Type 2 diabetes and heart palpitations were significantly associated with TS risk in males but not in females, whereas diseases of the respiratory system were associated with TS risk in females but not in males. This analysis provides further evidence of shared genetic and phenotypic architecture of different complex disorders., (© 2023. The Author(s).)

Attention-deficit/hyperactivity disorder (ADHD) is a highly heritable neurodevelopmental disorder, with onset in childhood and a considerable likelihood to persist into adulthood. Our previous work has identified that across adults and adolescents with ADHD, gray matter volume (GMV) alteration in the frontal cortex was consistently associated with working memory underperformance, and GMV alteration in the cerebellum was associated with inattention. Recent knowledge regarding ADHD genetic risk loci makes it feasible to investigate genomic factors underlying these persistent GMV alterations, potentially illuminating the pathology of ADHD persistence. Based on this, we applied a sparsity-constrained multivariate data fusion approach, sparse parallel independent component analysis, to GMV variations in the frontal and cerebellum regions and candidate risk single nucleotide polymorphisms (SNPs) data from 341 unrelated adult participants, including 167 individuals with ADHD, 47 unaffected siblings, and 127 healthy controls. We identified one SNP component significantly associated with one GMV component in superior/middle frontal regions and replicated this association in 317 adolescents from ADHD families. The association was stronger in individuals with ADHD than in controls, and stronger in adults and older adolescents than in younger ones. The SNP component highlights 93 SNPs in long non-coding RNAs mainly in chromosome 5 and 21 protein-coding genes that are significantly enriched in human neuron cells. Eighteen identified SNPs have regulation effects on gene expression, transcript expression, isoform percentage, or methylation level in frontal regions. Identified genes highlight MEF2C, CADM2, and CADPS2, which are relevant for modulating neuronal substrates underlying high-level cognition in ADHD, and their causality effects on ADHD persistence await further investigations. Overall, through a multivariate analysis, we have revealed a genomic pattern underpinning the frontal gray matter variation related to working memory deficit in ADHD., (© 2023. The Author(s).)

Despite a general decrease of attention-deficit/hyperactivity disorder (ADHD) symptoms during adolescence, these may persist in some individuals but not in others. Prior cross-sectional studies have shown that parenting style and their interaction with candidate genes are associated with ADHD symptoms. However, there is a lack of longitudinal research examining the independent and interactive effects of parenting and plasticity genes in predicting the course of attention-deficit/hyperactivity disorder (ADHD) symptoms across adolescence. Here, we investigated how children perceived their parents' parenting style (i.e., rejection, overprotection, and emotional warmth) at the age of 11, and their interaction with DRD4, MAOA, and 5-HTTLPR genotypes on parent-reported ADHD symptoms at three time points (mean ages 11.1, 13.4, and 16.2 years) in 1730 adolescents from the TRacking Adolescents' Individual Lives Survey (TRAILS). Growth Mixture Modeling in Mplus identified four ADHD symptom trajectories: low, moderate stable, high decreasing, and high persistent. Perceived parental rejection predicted class membership in the high persistent trajectory compared to the other classes (p < 0.001, odds ratios between 2.14 and 3.74). Gene-environment interactions were not significantly related to class membership. Our results indicate a role of perceived parental rejection in the persistence of ADHD symptoms. Perceived parental rejection should, therefore, be taken into consideration during prevention and treatment of ADHD in young adolescents., (© 2021. The Author(s).)

Background: Disruptive behavior in children and adolescents can manifest as reactive aggression and proactive aggression and is modulated by callous-unemotional traits and other comorbidities. Neural correlates of these aggression dimensions or subtypes and comorbid symptoms remain largely unknown. This multi-center study investigated the relationship between resting state functional connectivity (rsFC) and aggression subtypes considering comorbidities., Methods: The large sample of children and adolescents aged 8-18 years (n = 207; mean age = 13.30±2.60 years, 150 males) included 118 cases with disruptive behavior (80 with Oppositional Defiant Disorder and/or Conduct Disorder) and 89 controls. Attention-deficit/hyperactivity disorder (ADHD) and anxiety symptom scores were analyzed as covariates when assessing group differences and dimensional aggression effects on hypothesis-free global and local voxel-to-voxel whole-brain rsFC based on functional magnetic resonance imaging at 3 Tesla., Results: Compared to controls, the cases demonstrated altered rsFC in frontal areas, when anxiety but not ADHD symptoms were controlled for. For cases, reactive and proactive aggression scores were related to global and local rsFC in the central gyrus and precuneus, regions linked to aggression-related impairments. Callous-unemotional trait severity was correlated with ICC in the inferior and middle temporal regions implicated in empathy, emotion, and reward processing. Most observed aggression subtype-specific patterns could only be identified when ADHD and anxiety were controlled for., Conclusions: This study clarifies that hypothesis-free brain connectivity measures can disentangle distinct though overlapping dimensions of aggression in youths. Moreover, our results highlight the importance of considering comorbid symptoms to detect aggression-related rsFC alterations in youths., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Impaired emotion recognition is common in individuals with attention-deficit/hyperactivity disorder (ADHD) and may, via deficient emotion self-regulation, relate to the frequently co-occurring affective and social problems. The present study used an emotional face-matching task and functional magnetic resonance imaging (fMRI) to investigate neural responses during the processing of angry and fearful faces and visuo-spatial control stimuli. Additionally, measures for emotion dysregulation, ADHD type, and age were investigated in relation to the behavioral and neural fMRI data. We utilized a sample of 61 adolescents/young adults with ADHD and 51 age-matched healthy controls (age range: 12-28 years). Participants with ADHD had higher emotion dysregulation scores than controls. They also reacted slower and less accurate in response to emotional but not visuo-spatial control stimuli. Neural response differences between emotional and visuo-spatial trials were significantly smaller in cases, particularly in the left amygdala. While coupling between the right amygdala and bilateral ventromedial prefrontal cortex was stronger for emotional than visuo-spatial stimuli in control subjects, levels of positive coupling between the trial types did not significantly differ in participants with ADHD. Neither emotion dysregulation scores, nor ADHD type or age were related to the behavioral and neural processing alterations during the emotional face-matching task. Results indicate that emotion recognition deficits in ADHD are particularly associated with lower amygdala activation to emotional stimuli and alterations in the functional connections of the amygdala to medial prefrontal areas. Emotion recognition deficits and associated neural alterations were unrelated to emotion dysregulation, ADHD type, or age., (© 2021. The Author(s).)