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Contains fulltext : 307165.pdf (Publisher’s version ) (Open Access), Irritability worsens prognosis and increases mortality in individuals with Attention-Deficit and Hyperactivity Disorder (ADHD) and/or Borderline Personality Disorder (BPD). However, treatment options are still insufficient. The aim of this randomized, double blind, placebo-controlled study was to investigate the superiority of a synbiotic over placebo in the management of adults with ADHD and/or BPD and high levels of irritability. The study was conducted between February 2019 and October 2020 at three European clinical centers located in Hungary, Spain and Germany. Included were patients aged 18-65 years old diagnosed with ADHD and/or BPD and high levels of irritability (i.e., an Affectivity Reactivity Index (ARI-S) ≥ 5, plus a Clinical Global Impression-Severity Scale (CGI-S) score ≥ 4). Subjects were randomized 1(synbiotic):1(placebo); the agent was administered each day, for 10 consecutive weeks. The primary outcome measure was end-of-treatment response (i.e., a reduction ≥ 30 % in the ARI-S total score compared to baseline, plus a Clinical Global Impression-Improvement (CGI-I) total score of < 3 (very much, or much improved), at week 10). Between-treatment differences in secondary outcomes, as well as safety were also investigated. Of the 231 included participants, 180 (90:90) were randomized and included in the intention-to-treat-analyses. Of these, 117 (65 %) were females, the mean age was 38 years, ADHD was diagnosed in 113 (63 %), BPD in 44 (24 %), both in 23 (13 %). The synbiotic was well tolerated. At week 10, patients allocated to the synbiotic showed a significantly higher response rate compared to those allocated to placebo (OR: 0.2, 95 % CI:0.1 to 0.7; P = 0.01). These findings suggest that that (add-on) treatment with a synbiotic may be associated with a clinically meaningful improvement in irritability in, at least, a subgroup of adults with ADHD and/or BPD. A superiority of the synbiotic over placebo in the management of emotional dysregulation (-3, 15 juni 2024

Radboud University, 03 mei 2024, Promotores : Rommelse, N.N.J., Buitelaar, J.K. Co-promotor : Berg, S.W. van den, Contains fulltext : 305474.pdf (Publisher’s version ) (Open Access)

Item does not contain fulltext, 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.

Contains fulltext : 296362.pdf (Publisher’s version ) (Open Access), There is an ongoing debate as to whether autism spectrum disorder (ASD) is expressed differently in women than men. It is unclear whether differences found are specific to autism or merely reflecting normative development. In this study, we compared sex differences in developmental trajectories of autistic and co-occurring psychopathological symptoms in adolescents with milder forms of autism to those in a normative group matched for intelligence quotient (IQ) and socioeconomic status. Data of five assessment waves from ages 11 to 22 years were analyzed using linear mixed modeling. We found that in adolescence, sex differences in developmental trajectories of psychopathological symptoms specific for autism are confined to the repetitive stereotyped domain (males had higher scores on the sensory/stereotypic and resistance to change domains, the latter difference disappeared during adolescence due to an increase of these problems in females with ASD). Other sex differences, among which an increase over time in affective and anxiety problems in females was the most outstanding, were also observed in typically developing females. These sex-specific differences have relevance in the clinical care of men and women with autism, although they are subtle compared to differences between individuals with and without autism, which are broadly present in internalizing and externalizing problem domains.Lay abstractThere is an ongoing debate as to whether autism spectrum disorder (ASD) is expressed differently in women than men. Studies on sex differences in autistic symptoms and symptoms of other psychiatric problems present in individuals with autism generally do not include a general population comparison group, making it unclear whether differences are specific to autism or merely reflecting development in the general population. In this study, we compared sex differences in the course of autistic and at the same time present symptoms of other psychiatric problems in adolescen

Contains fulltext : 294945.pdf (Publisher’s version ) (Open Access), BACKGROUND: A lifestyle including poor diet, physical inactivity, excessive gaming and inadequate sleep hygiene is frequently seen among Dutch children. These lifestyle behaviors can cause long-term health problems later in life. Unhealthy lifestyle and poor physical health are even more prevalent among children with mental illness (MI) such as autism, attention-deficit/hyperactivity disorder, depression, and anxiety. However, research on lifestyle interventions among children with MI is lacking. As a result, there are currently no guidelines, or treatment programs where children with MI and poor lifestyle can receive effective support. To address these issues and to provide insight into the effectiveness of lifestyle interventions in children with MI and their families, the Movementss study was designed. This paper describes the rationale, study design, and methods of an ongoing randomized controlled trial (RCT) comparing the short-term (12 weeks) and long-term (1 year) effects of a lifestyle intervention with care as usual (CAU) in children with MI and an unhealthy lifestyle. METHODS: A total of 80 children (6-12 years) with MI according to DSM-V and an unhealthy lifestyle are randomized to the lifestyle intervention group or CAU at a specialized child and adolescent mental hospital. The primary outcome measure is quality of life measured with the KIDSCREEN. Secondary outcomes include emotional and behavior symptoms, lifestyle parameters regarding diet, physical activity, sleep, and screen time, cognitive assessment (intelligence and executive functions), physical measurements (e.g., BMI), parenting styles, and family functioning, prior beliefs, adherence, satisfaction, and cost-effectiveness. Assessments will take place at the start of the study (T0), after 12 weeks (T1), six months (T2), and 12 months of baseline (T3) to measure long-term effects. DISCUSSION: This RCT will likely contribute to the currently lacking knowledge on lifestyle interventions in childre

11 juli 2023, Contains fulltext : 295281.pdf (Publisher’s version ) (Open Access), 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

Contains fulltext : 295441.pdf (Publisher’s version ) (Open Access), Background: Emotion dysregulation (ED) is increasingly under investigation as a cross-disorder trait, and is by some considered as the core feature in mental disorders. The aims of this study were to scrutinize the overlapping and distinct characteristics of ED for internalizing, externalizing and neurodevelopmental disorders and to identify the most pertinent ED characteristics to guide clinicians in treatment choice. Methods: Information on clinical diagnosis (Attention Deficit/Hyperactivity Disorder ADHD, Autism Spectrum Disorder, Oppositional Defiant Disorder/Conduct Disorder, Anxiety and Mood Disorders), ED (measured by the CBCL-Emotion Dysregulation Index), Quality of Life (Qol, measured by the Kidscreen-27), and treatment duration (measured by Electronic Health Records) was retrieved from two large samples of toddlers (1.5–5 year old; N = 1,544) and school aged children (6–18 year old; N = 7,259). Frequency scores and logistic regression were used to study symptom profiles of ED, as measured with CBCL-EDI, across all disorders. Linear regression was used to determine the predictive value of ED (CBCL-EDI total score) regarding QoL and treatment duration in addition to—and in interaction with—clinical diagnosis. Results: Across disorders, equal levels of total ED were found, which predicted lower QoL and a longer treatment duration in addition to clinical diagnosis. The majority of items (11/15 and 16/18) were of equal relevance to the disorders; items that were not, largely reflected disorder specific DSM definitions (i.e., externalizing symptoms in ODD/CD and internalizing symptoms in Anxiety and Mood disorders). Conclusion: ED is a clinically useful cross-disorder trait to predict severity of impairment as well as required treatment duration. In addition, ED is largely composed of shared features across disorders, with certain disorder specific colored elements.

Radboud University, 19 april 2022, Promotores : Franke, B., Buitelaar, J.K., Lambregts-Rommelse, N.N.J. Co-promotor : Roth Mota, N., Contains fulltext : 247713.pdf (Publisher’s version ) (Open Access)

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Contains fulltext : 281503.pdf (Publisher’s version ) (Open Access), Attention-Deficit Hyperactivity Disorder (ADHD) is a complex and heterogeneous neurodevelopmental condition for which curative treatments are lacking. Whilst pharmacological treatments are generally effective and safe, there is considerable inter-individual variability among patients regarding treatment response, required dose, and tolerability. Many of the non-pharmacological treatments, which are preferred to drug-treatment by some patients, either lack efficacy for core symptoms or are associated with small effect sizes. No evidence-based decision tools are currently available to allocate pharmacological or psychosocial treatments based on the patient's clinical, environmental, cognitive, genetic, or biological characteristics. We systematically reviewed potential biomarkers that may help in diagnosing ADHD and/or stratifying ADHD into more homogeneous subgroups and/or predict clinical course, treatment response, and long-term outcome across the lifespan. Most work involved exploratory studies with cognitive, actigraphic and EEG diagnostic markers to predict ADHD, along with relatively few studies exploring markers to subtype ADHD and predict response to treatment. There is a critical need for multisite prospective carefully designed experimentally controlled or observational studies to identify biomarkers that index inter-individual variability and/or predict treatment response.

Contains fulltext : 243902.pdf (Publisher’s version ) (Open Access), This study investigated the genetic components of ADHD and ASD by examining the cross-disorder trait of emotion recognition problems. The genetic burden for ADHD and ASD on previously identified emotion recognition factors (speed and accuracy of visual and auditory emotion recognition) and classes (Class 1: Average visual, impulsive auditory; Class 2: Average-strong visual & auditory; Class 3: Impulsive & imprecise visual, average auditory; Class 4: Weak visual & auditory) was assessed using ASD and ADHD polygenic risk scores (PRS). Our sample contained 552 participants: 74 with ADHD, 85 with ASD, 60 with ASD + ADHD, 177 unaffected siblings of ADHD or ASD probands, and 156 controls. ADHD- and ASD-PRS, calculated from the latest ADHD and ASD GWAS meta-analyses, were analyzed across these emotion recognition factors and classes using linear mixed models. Unexpectedly, the analysis of emotion recognition factors showed higher ASD-PRS to be associated with faster visual emotion recognition. The categorical analysis of emotion recognition classes showed ASD-PRS to be reduced in Class 3 compared to the other classes (p value threshold [pT] = 1, p = .021). A dimensional analysis identified a high ADHD-PRS reduced the probability of being assigned to the Class 1 or Class 3 (pT = .05, p = .028 and p = .044, respectively). Though these nominally significant results did not pass FDR correction, they potentially indicate different indirect causative chains from genetics via emotion recognition to ADHD and ASD, which need to be verified in future research.

Item does not contain fulltext, BACKGROUND: There is an increased interest in 'late-onset' attention-deficit/hyperactivity disorder (ADHD), referring to the onset of clinically significant ADHD symptoms after the age of 12 years. This study aimed to examine whether unaffected siblings with late-onset ADHD could be differentiated from stable unaffected siblings by their neurocognitive functioning in childhood. METHODS: We report findings from a 6-year prospective, longitudinal study of the Dutch part of the International Multicenter ADHD Genetics (IMAGE) study, including individuals with childhood-onset (persistent) ADHD (n = 193), their siblings with late-onset ADHD (n = 34), their stable unaffected siblings (n = 111) and healthy controls (n = 186). At study entry (mean age: 11.3) and follow-up (mean age: 17.01), participants were assessed for ADHD by structured psychiatric interviews and multi-informant questionnaires. Several neurocognitive functions were assessed at baseline and after 6 years, including time reproduction, timing variability (reaction time variability and time production variability), reaction time speed, motor control and working memory; intelligence was taken as a measure of overall neurocognitive functioning. RESULTS: Siblings with late-onset ADHD were similar to individuals with childhood-onset ADHD in showing longer reaction times and/or higher error rates on all neurocognitive measures at baseline and follow-up, when compared to healthy controls. They differed from stable unaffected siblings (who were similar to healthy controls) by greater reaction time variability and timing production variability at baseline. No significant group by time interaction was found for any of the tasks. CONCLUSIONS: For unaffected siblings of individuals with ADHD, reaction time variability and timing production variability may serve as neurocognitive marker for late-onset ADHD.

Radboud University, 20 januari 2021, Promotores : Buitelaar, J.K., Lambregts-Rommelse, N.N.J., Contains fulltext : 228600.pdf (publisher's version ) (Open Access)

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Inaugurele rede als hoogleraar aan de Radboud Universiteit / Faculteit der Medische Wetenschappen en Karakter met de leeropdracht Neurobiologische ontwikkelingsstoornissen, 16 juni 2021, Contains fulltext : 234183.pdf (Publisher’s version ) (Open Access)

Contains fulltext : 220445.pdf (publisher's version ) (Open Access), The 14-3-3 protein family are molecular chaperones involved in several biological functions and neurological diseases. We previously pinpointed YWHAZ (encoding 14-3-3ζ) as a candidate gene for autism spectrum disorder (ASD) through a whole-exome sequencing study, which identified a frameshift variant within the gene (c.659-660insT, p.L220Ffs*18). Here, we explored the contribution of the seven human 14-3-3 family members in ASD and other psychiatric disorders by investigating the: (i) functional impact of the 14-3-3ζ mutation p.L220Ffs*18 by assessing solubility, target binding and dimerization; (ii) contribution of common risk variants in 14-3-3 genes to ASD and additional psychiatric disorders; (iii) burden of rare variants in ASD and schizophrenia; and iv) 14-3-3 gene expression using ASD and schizophrenia transcriptomic data. We found that the mutant 14-3-3ζ protein had decreased solubility and lost its ability to form heterodimers and bind to its target tyrosine hydroxylase. Gene-based analyses using publicly available datasets revealed that common variants in YWHAE contribute to schizophrenia (p = 6.6 × 10(-7)), whereas ultra-rare variants were found enriched in ASD across the 14-3-3 genes (p = 0.017) and in schizophrenia for YWHAZ (meta-p = 0.017). Furthermore, expression of 14-3-3 genes was altered in post-mortem brains of ASD and schizophrenia patients. Our study supports a role for the 14-3-3 family in ASD and schizophrenia.

Contains fulltext : 217550.pdf (publisher's version ) (Open Access), Background: There is an ongoing debate as to whether attention-deficit hyperactivity disorder (ADHD) in highly intelligent individuals has a similar presentation as in average intelligent individuals. The aim of this study was to examine the cognitive correlates of ADHD in highly intelligent children and adolescents with ADHD. Method: Two independent samples (N = 204 and N = 84) of (1) high intelligence quotient (IQ) (IQ >= 120) children and adolescents with ADHD were used, carefully matched on age, gender, ADHD severity, and IQ with (2) control participants with high intelligence, (3) participants with ADHD with an average intelligence (IQ 90-110), and (4) control participants with an average intelligence. These samples were selected from the Dutch node of the International Multicenter ADHD Genetics (NeuroIMAGE) and Tracking Adolescents' Individual Lives Survey (TRAILS) cohorts, respectively, in which a large battery of cognitive tasks was administered. Linear mixed models were used to examine the main effects of ADHD and IQ and their interaction on cognitive performance. Results: ADHD-control group differences were not moderated by IQ; mostly equally large ADHD-control differences in cognitive performance were found for high versus average intelligent groups. The small moderating effects found mostly indicated somewhat milder cognitive problems in highly intelligent individuals with ADHD. Overall, highly intelligent children and adolescents with ADHD performed at the level of the average intelligent control children. Conclusions: Our findings indicate the cognitive profile of ADHD is similar in highly versus average intelligent individuals with ADHD, although ADHD-related cognitive deficits may be easily overlooked in the high intelligence population when compared to the typical (i.e., average intelligent) control group.

Contains fulltext : 214790.pdf (Publisher’s version ) (Closed access), The aim of the current study was to compare levels of oxytocin, cortisol, and testosterone in adolescents with either autism spectrum disorder (ASD), or oppositional defiant disorder (ODD)/conduct disorder (CD), and in typically developing individuals (TDI), and relate hormone levels to severity and subtype of aggression and callous-unemotional (CU) traits. Saliva concentrations of oxytocin, cortisol, and testosterone were assessed in 114 male participants (N = 49 ASD, N = 37 ODD/CD, N = 28 TDI,) aged 12-19 years (M = 15.4 years, SD = 1.9). The ASD and the ODD/CD groups had significantly lower levels of oxytocin than the TDI group, and the ODD/CD group had significantly higher levels of testosterone than the ASD group. There were no group effects on cortisol levels. Group differences remained for oxytocin after correcting for the influence of CU traits, but were not significant after controlling for aggression. Results for testosterone became non-significant after correction for either CU traits or aggression. Across groups, higher levels of CU traits were related to higher levels of cortisol and testosterone, however, proactive and reactive aggression were unrelated to all three hormonal levels. The current findings show that, regardless of cognitive ability or comorbid disorders, the diagnostic groups (ASD, ODD/CD) differ from each other by their hormonal levels, with the ASD group characterized by relative low level of oxytocin, and the ODD/CD group by a relative low level of oxytocin and high level of testosterone. These group effects were partly driven by differences in CU traits between the groups.

Contains fulltext : 229208.pdf (Publisher’s version ) (Closed access)

Contains fulltext : 229260.pdf (publisher's version ) (Open Access), Most genes associated with neurodevelopmental disorders (NDDs) were identified with an excess of de novo mutations (DNMs) but the significance in case-control mutation burden analysis is unestablished. Here, we sequence 63 genes in 16,294 NDD cases and an additional 62 genes in 6,211 NDD cases. By combining these with published data, we assess a total of 125 genes in over 16,000 NDD cases and compare the mutation burden to nonpsychiatric controls from ExAC. We identify 48 genes (25 newly reported) showing significant burden of ultra-rare (MAF < 0.01%) gene-disruptive mutations (FDR 5%), six of which reach family-wise error rate (FWER) significance (p < 1.25E-06). Among these 125 targeted genes, we also reevaluate DNM excess in 17,426 NDD trios with 6,499 new autism trios. We identify 90 genes enriched for DNMs (FDR 5%; e.g., GABRG2 and UIMC1); of which, 61 reach FWER significance (p < 3.64E-07; e.g., CASZ1). In addition to doubling the number of patients for many NDD risk genes, we present phenotype-genotype correlations for seven risk genes (CTCF, HNRNPU, KCNQ3, ZBTB18, TCF12, SPEN, and LEO1) based on this large-scale targeted sequencing effort.

Contains fulltext : 217818.pdf (Publisher’s version ) (Closed access), Het intelligentieniveau van kinderen en adolescenten met een autismespectrumstoornis (ASS) kan binnen deze groep enorm variëren. Het doel van de studie was het onderzoeken van de absolute en relatieve ernst van de neuropsychologische problemen van kinderen en adolescenten met ASS afhankelijk van hun IQ.

Contains fulltext : 220099.pdf (publisher's version ) (Open Access)

Contains fulltext : 218284.pdf (publisher's version ) (Open Access), Attention-deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental disorder. Given the growing evidence of gut microbiota being involved in psychiatric (including neurodevelopmental) disorders, we aimed to identify differences in gut microbiota composition between participants with ADHD and controls and to investigate the role of the microbiota in inattention and hyperactivity/impulsivity. Fecal samples were collected from 107 participants (NADHD = 42; Ncontrols = 50; NsubthreholdADHD = 15; range age: 13-29 years). The relative quantification of bacterial taxa was done using 16S ribosomal RNA gene amplicon sequencing. Beta-diversity revealed significant differences in bacterial composition between participants with ADHD and healthy controls, which was also significant for inattention, but showing a trend in case of hyperactivity/impulsivity only. Ten genera showed nominal differences (p < 0.05) between both groups, of which seven genera were tested for their association with ADHD symptom scores (adjusting for age, sex, body mass index, time delay between feces collection and symptoms assessment, medication use, and family relatedness). Our results show that variation of a genus from the Ruminococcaceae family (Ruminococcaceae_UCG_004) is associated (after multiple testing correction) with inattention symptoms and support the potential role of gut microbiota in ADHD pathophysiology.

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Contains fulltext : 213540.pdf (publisher's version ) (Open Access), The widely reported association between ADHD and overweight may be attributable to genetic and environmental factors also present in unaffected family members. Therefore, the purpose of this study was to examine the association between ADHD and overweight within families. A cohort was used of families with at least one member with ADHD, recruited as part of the Dutch node of the International Multicenter ADHD Genetics (IMAGE) study, with assessments taking place between 2003 and 2006, 2009 and 2012, and 2013 and 2015. The three assessment waves yielded N = 1828 youth assessments and N = 998 parent assessments from N = 447 unique families. Overweight was defined as a body mass index (BMI) >= 85th percentile for youth of the same age and sex; overweight in adults as a BMI >= 25. Effects of age, gender, and medication use (psychostimulants, antipsychotics, and melatonin) were taken into account. Generalized estimation equations were used to correct for within-family and within-subject correlations. There was no difference in risk between ADHD-affected youth and their unaffected siblings (OR 0.92, 95% CI 0.78-1.09). However, compared to population prevalence data, all ADHD family members alike were at increased risk for being overweight: ADHD-affected youth (OR 1.33, 95% CI 1.13-1.59), unaffected siblings (OR 1.73, 95% CI 1.45-2.08), mothers (OR 1.74, 95% CI 1.40-2.17) and fathers (OR 1.78, 95% CI 1.46-2.15). Parental overweight - but not parental ADHD - was predictive of offspring overweight (mothers OR 1.40; 95% CI 1.14-1.73, fathers OR 1.83; 95% CI 1.41-2.36). Being overweight runs in ADHD families, yet is not specifically linked to ADHD within families. Shared unhealthy lifestyle factors (including nutrition, sleep, exercise, stress) as well as genetic factors shared by family members likely explain the findings.

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Contains fulltext : 203257.pdf (publisher's version ) (Open Access), This longitudinal study focused on early behavioural problems and autistic traits. In a stratified, population-derived sample of 119 children, mothers reported through questionnaires on externalizing, internalizing, and social-communicative characteristics of their child in infancy (14 months) and toddlerhood (37 months), and on autistic traits at preschool age (4-5 years). Children with consistently normal behaviour from infancy to toddlerhood showed lower autistic traits at preschool age than children with deviant behaviour on one or both time points. High autistic traits at preschool age were predominantly preceded by problems in interaction, communication, language, play, and affect in infancy and/or toddlerhood, but also by inattention in toddlerhood. Adequate support and specific interventions in these domains are needed in an attempt to diminish further derailment of the child's behaviour and development, and to prevent the full manifestation of ASD or related disorders such as ADHD.

Contains fulltext : 201032pre.pdf (preprint version ) (Open Access)

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Contains fulltext : 208570.pdf (publisher's version ) (Open Access), Adolescents with attention-deficit/hyperactivity disorder (ADHD) are at increased risk of developing substance use disorders (SUDs) and nicotine dependence (ND). It remains unclear whether and how stimulant treatment may affect this risk. We aimed to investigate how stimulant use profiles influence the risk of SUDs and ND, using a novel data-driven community detection analysis to construct different stimulant use profiles. Comprehensive lifetime stimulant prescription data and data on SUDs and ND were available for 303 subjects with ADHD and 219 controls, with a mean age 16.3 years. Community detection was used to define subgroups based on multiple indicators of treatment history, start age, treatment duration, total dose, maximum dose, variability, stop age. In stimulant-treated participants, three subgroups with distinct medication trajectories were distinguished (late-and-moderately dosed, n = 91; early-and-moderately dosed, n = 51; early-and-intensely dosed, n = 103). Compared to stimulant-naive participants (n = 58), the early-and-intense treatment group had a significantly lower risk of SUDs and ND (HR = 0.28, and HR = 0.29, respectively), while the early-and-moderate group had a significantly lower risk of ND only (HR = 0.30). The late-and-moderate group was at a significantly higher risk of ND compared to the other two treatment groups (HR = 2.66 for early-and-moderate, HR = 2.78 for early-and-intense). Our findings show that in stimulant-treated adolescents with ADHD, long-term outcomes are associated with treatment characteristics, something that is often ignored when treated individuals are compared to untreated individuals.

Contains fulltext : 201728.pdf (postprint version ) (Open Access) Contains fulltext : 201728sup.pdf (postprint version ) (Open Access), Background: Efavirenz is commonly prescribed for children with HIV infection, yet little is known about risks of neuropsychiatric side-effects. We aimed to compare competence (social involvement, activities, and school performance) and psychopathology (internalising and externalising problems), cognitive performance (intelligence and working memory), and adherence in Tanzanian children on an efavirenz-based versus a non-efavirenz-based regimen. Methods: In this multicentre, cross-sectional, observational study, we included consecutive children (aged 6-12 years) with HIV infection, on combination antiretroviral therapy (cART) for at least 6 months, and with viral loads of less than 1000 copies per mL from HIV care clinics of three primary health facilities and three referral hospitals in Moshi, Kilimanjaro, Tanzania. Children with acute illnesses, medication switch in the 6 months before the study visit, and any history of brain injury or developmental delay before cART initiation were excluded. All interviews and assessments were done by trained local research nurses under the supervision of a medical doctor. The primary outcomes, competence and psychopathology, were measured with the Child Behavior Checklist. We used ANCOVA to assess differences between groups. This study is registered with ClinicalTrials.gov, number NCT03227653. Findings: Between June 19, 2017, and Dec 14, 2017, 141 children were analysed, of whom 72 (51%) used efavirenz-based cART and 69 (49%) used non-efavirenz-based cART. After controlling for age, sex, and clinical and demographic confounders, we observed lower competence (adjusted mean difference -2·43 [95% CI -4·19 to -0·67], p=0·0071), largely driven by lower school performance scores (adjusted mean difference -0·91 [-1·42 to -0·40], p=0·00055), in the efavirenz group than in the non-efavirenz group. More total (adjusted mean difference 5·96 [95% CI -1·12 to 13·04], p=0·098) and internalising (adjusted mean difference 2·00 [-0·29 to 4·29]

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Contains fulltext : 205889.pdf (publisher's version ) (Closed access), Oppositional defiant disorder, conduct disorder (ODD/CD), and autism spectrum disorder (ASD) share poor empathic functioning and have been associated with impaired emotional processing. However, no previous studies directly compared similarities and differences in these processes for the two disorders. A two-choice emotional valence detection task requiring differentiation between positive, negative, and neutral IAPS pictures was administered to 52 adolescents (12-19 years) with ODD/CD, 52 with ASD and 24 typically developing individuals (TDI). Callous–unemotional (CU) traits were assessed by self- and parent reports using the Inventory of callous–unemotional traits. Main findings were that adolescents with ODD/CD or ASD both performed poorer than TDI in terms of accuracy, yet only the TDI - not both clinical groups - had relatively most difficulty in discriminating between positive versus neutral pictures compared to neutral-negative or positive-negative contrasts. Poorer performance was related to a higher level of CU traits. The results of the current study suggest youth with ODD/CD or ASD have a diminished ability to detect emotional valence which is not limited to facial expressions and is related to a higher level of CU traits. More specifically, youth with ODD/CD or ASD seem to have a reduced processing of positive stimuli and/or lack a 'positive perception bias' present in TDI that could either contribute to the symptoms and/or be a result of having the disorder and may contribute to the comorbidity of both disorders.

Contains fulltext : 193210.pdf (publisher's version ) (Open Access), Research on sex-related differences in Autism Spectrum Disorder (ASD) has been impeded by small samples. We pooled 28 datasets from 18 sites across nine European countries to examine sex differences in the ASD phenotype on the ADI-R (376 females, 1763 males) and ADOS (233 females, 1187 males). On the ADI-R, early childhood restricted and repetitive behaviours were lower in females than males, alongside comparable levels of social interaction and communication difficulties in females and males. Current ADI-R and ADOS scores showed no sex differences for ASD severity. There were lower socio-communicative symptoms in older compared to younger individuals. This large European ASD sample adds to the literature on sex and age variations of ASD symptomatology.

Contains fulltext : 184153.pdf (publisher's version ) (Open Access), Interference control refers to the ability to selectively attend to certain information while ignoring distracting information. This ability can vary as a function of distractor relevance. Distractors that are particularly relevant to an individual may attract more attention than less relevant distractors. This is referred to as attention bias. Weak interference control and altered reward sensitivity are both important features of attention deficit hyperactivity disorder (ADHD). However, interference control is typically studied in isolation. This study integrates both. Youths (aged 9 to 17 years) with ADHD (n = 37, 25 boys) and typically-developing controls (n = 38, 20 boys) completed a Stroop task using appetitive words and matched neutral words to assess whether appetitive distractors diminished interference control more in youths with ADHD than controls. In order to test for specificity, aversive words were also included. As expected, appetitive words disrupted interference control but this effect was not stronger for youths with ADHD than the controls. Aversive words, on the other hand, facilitated interference control. Dimensional analyses revealed that this facilitation effect increased substantially as a function of ADHD symptom severity. Possible mechanisms for this effect include up-regulation of interference control as a function of induced negative mood, or as a function of increased effort. In conclusion, appetitive words do not lead to worse interference control in youths with ADHD compared with controls. Interference control was modulated in a valence-specific manner, concurrent with mood-induced effects on cognitive control.

Contains fulltext : 190664.pdf (publisher's version ) (Open Access), BACKGROUND: The risk for major depression and obesity is increased in adolescents and adults with attention-deficit / hyperactivity disorder (ADHD) and adolescent ADHD predicts adult depression and obesity. Non-pharmacological interventions to treat and prevent these co-morbidities are urgently needed. Bright light therapy (BLT) improves day-night rhythm and is an emerging therapy for major depression. Exercise intervention (EI) reduces obesity and improves depressive symptoms. To date, no randomized controlled trial (RCT) has been performed to establish feasibility and efficacy of these interventions targeting the prevention of co-morbid depression and obesity in ADHD. We hypothesize that the two manualized interventions in combination with mobile health-based monitoring and reinforcement will result in less depressive symptoms and obesity compared to treatment as usual in adolescents and young adults with ADHD. METHODS: This trial is a prospective, pilot phase-IIa, parallel-group RCT with three arms (two add-on treatment groups [BLT, EI] and one treatment as usual [TAU] control group). The primary outcome variable is change in the Inventory of Depressive Symptomatology total score (observer-blinded assessment) between baseline and ten weeks of intervention. This variable is analyzed with a mixed model for repeated measures approach investigating the treatment effect with respect to all three groups. A total of 330 participants with ADHD, aged 14 - < 30 years, will be screened at the four study centers. To establish effect sizes, the sample size was planned at the liberal significance level of alpha = 0.10 (two-sided) and the power of 1-beta = 80% in order to find medium effects. Secondary outcomes measures including change in obesity, ADHD symptoms, general psychopathology, health-related quality of life, neurocognitive function, chronotype, and physical fitness are explored after the end of the intervention and at the 12-week follow-up. DISCUSSION: This is the fi

Contains fulltext : 194129.pdf (publisher's version ) (Open Access)

Contains fulltext : 199340.pdf (publisher's version ) (Open Access), Background: Attention-deficit/hyperactivity disorder (ADHD) is associated with substance use disorders (SUD; alcohol and/or drug dependence) and nicotine dependence. This study aims to advance our knowledge about the association between SUD, nicotine dependence, and the course of ADHD (persistent versus remittent ADHD and late-onset ADHD). Methods: ADHD, SUD, and nicotine dependence were longitudinally assessed (mean age at study entry 11.3 years, mean age at follow-up 21.1 years) using structured psychiatric interviews and multi-informant questionnaires in a subsample of the Dutch part of the International Multicenter ADHD Genetics study. Individuals with persistent ADHD (n = 62), remittent ADHD (n = 12), late-onset ADHD (n = 18; age of onset after 12 years), unaffected siblings (n = 50), and healthy controls (n = 47) were assessed. Hazard ratios (HR) with 95% confidence intervals (CIs) were estimated by Cox regression and adjusted for clustered family data, gender, follow-up length, and current age. Results: Individuals with persistent ADHD were at significantly higher risk of development of SUD relative to healthy controls (HR = 4.56, CI 1.17-17.81). In contrast, levels of SUD in those with remittent ADHD were not different from healthy controls (HR = 1.00, CI .07-13.02). ADHD persisters had also higher prevalence rates of nicotine dependence (24.2%) than ADHD remitters (16.7%) and healthy controls (4.3%). A similar pattern was found in initially unaffected siblings who met ADHD criteria at follow-up ("late-onset" ADHD); they had also a higher prevalence of SUD (33%) compared to stable unaffected siblings (20%) and were at significantly increased risk of development of nicotine dependence compared to healthy controls (HR = 13.04, CI 2.08–81.83). Conclusions: SUD and nicotine dependence are associated with a negative ADHD outcome. Results further emphasize the need for clinicians to comprehensively assess substance use when diagnosing ADHD in adolescents and adult

Contains fulltext : 190645.pdf (publisher's version ) (Closed access), BACKGROUND: Autism spectrum disorders (ASD) are characterized by substantial clinical, etiological and neurobiological heterogeneity. Despite this heterogeneity, previous imaging studies have highlighted the role of specific cortical and subcortical structures in ASD and have forwarded the notion of an ASD specific neuroanatomy in which abnormalities in brain structures are present that can be used for diagnostic classification approaches. METHOD: A large (N = 859, 6-27 years, IQ 70-130) multi-center structural magnetic resonance imaging dataset was examined to specifically test ASD diagnostic effects regarding (sub)cortical volumes. RESULTS: Despite the large sample size, we found virtually no main effects of ASD diagnosis. Yet, several significant two- and three-way interaction effects of diagnosis by age by gender were found. CONCLUSION: The neuroanatomy of ASD does not exist, but is highly age and gender dependent. Implications for approaches of stratification of ASD into more homogeneous subtypes are discussed.

Contains fulltext : 198098.pdf (publisher's version ) (Open Access), Background: Emotion recognition dysfunction has been reported in both autism spectrum disorders (ASD) and attention-deficit/hyperactivity disorder (ADHD). This suggests that emotion recognition is a cross-disorder trait that may be utilised to understand the heterogeneous psychopathology of ASD and ADHD. We aimed to identify emotion recognition subtypes and to examine their relation with quantitative and diagnostic measures of ASD and ADHD to gain further insight into disorder comorbidity and heterogeneity. Methods: Factor mixture modelling was used on speed and accuracy measures of auditory and visual emotion recognition tasks. These were administered to children and adolescents with ASD (N = 89), comorbid ASD + ADHD (N = 64), their unaffected siblings (N = 122), ADHD (N = 111), their unaffected siblings (N = 69), and controls (N = 220). Identified classes were compared on diagnostic and quantitative symptom measures. Results: A four-class solution was revealed, with the following emotion recognition abilities: (1) average visual, impulsive auditory; (2) average-strong visual and auditory; (3) impulsive/imprecise visual, average auditory; (4) weak visual and auditory. The weakest performing class (4) contained the highest percentage of patients (66.07%) and the lowest percentage controls (10.09%), scoring the highest on ASD/ADHD measures. The best performing class (2) demonstrated the opposite: 48.98% patients, 15.26% controls with relatively low scores on ASD/ADHD measures. Conclusions: Subgroups of youths can be identified that differ both in quantitative and qualitative aspects of emotion recognition abilities. Weak emotion recognition abilities across sensory domains are linked to an increased risk for ASD as well as ADHD, although emotion recognition impairments alone are neither necessary nor sufficient parts of these disorders.

Contains fulltext : 191296.pdf (publisher's version ) (Closed access), The field of early autism research is in dire need of outcome measures that adequately reflect subtle changes in core autistic behaviors. This article compares the ability of a newly developed measure, the Brief Observation of Social Communication Change (BOSCC), and the Autism Diagnostic Observation Schedule (ADOS) to detect changes in core symptoms of autism in 44 toddlers. The results provide encouraging evidence for the Brief Observation of Social Communication Change as a candidate outcome measure, as reflected in sufficient inter- and intra-rater reliability, independency from other child characteristics, and sensitivity to capture change. Although the Brief Observation of Social Communication Change did not evidently outperform the Autism Diagnostic Observation Schedule on any of these quality criteria, the instrument may be better able to capture subtle, individual changes in core autistic symptoms. The promising findings warrant further study of this new instrument.