Study Protocol: Pegasus: psychotherapy incorporating horses for 'therapy-resistant' adolescents with autism spectrum disorders, a study with series of randomised, baseline controlled n-of-1 trials.

BACKGROUND: For people with autism spectrum disorder (ASD), daily life can be highly stressful with many unpredictable events that can evoke emotion dysregulation (ED): a strong difficulty with appropriately negative affect regulation. For some of the patients with ASD, treatment as usual does not prove to be effective for ED. They may be at risk of life-long impairment, development of other disorders and loss of motivation for most regular forms of therapy. A highly promising method that may prove effective for therapy-resistant individuals with ASD is Psychotherapy incorporating horses (PIH). PIH uses the interactions of the horse and the patients on the ground and does not include horseriding. While often met with prejudgment and scepticism, reports from parents and therapists as well as a recent systematic review suggest that PIH may have beneficial effects on youths with ASD. Therefore, we examine clinical outcomes both in the short and in the long terms of PIH offered to adolescents with ASD and severe ED despite regular therapy. METHODS: A total of 35 adolescents aged 11-18 years with ASD will receive PIH during 15 sessions once a week with randomization to five different groups differentiating in baseline phase from 2 to 6 weeks. PIH uses horses to promote social awareness and self-awareness as well as relationship management and self-management. The primary outcome is the response to treatment on the Emotion Dysregulation Index (EDI). The secondary outcome measures include ASD symptom severity, quality of life, self-esteem, global and family functioning, and goal attainment. Assessments take place at the baseline (T0), at the end of baseline phase A (T1), after completion of intervention phase B (T2), after the end of post-measurement phase C (T3) and after one year (T4). Qualitative interviews of participants, parents and therapists will be held to reveal facilitators and barriers of PIH and a cost-effectiveness study will be performed. DISCUSSION: This study aims at contributing to clinical practice for adolescents with ASD and persistent emotion regulation problems despite 1.5 year of treatment by offering Psychotherapy incorporating horses in a study with series of randomised, baseline controlled n-of-1 trials. TRIAL REGISTRATION: www. CLINICALTRIALS: gov NCT05200351, December 10th 2021.

Efficacy of a synbiotic in the management of adults with Attention-Deficit and Hyperactivity Disorder and/or Borderline Personality Disorder and high levels of irritability: Results from a multicenter, randomized, placebo-controlled, "basket" trial.

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 experienced 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 (-3.6, 95 % CI:-6.8 to -0.3; P = 0.03), emotional symptoms (-0.6, 95 % CI:-1.2 to -0.05; P = 0.03), inattention (-1.8, 95 % CI: -3.2 to -0.4; P = 0.01), functioning (-2.7, 95 % CI: -5.2 to -0.2; P = 0.03) and perceived stress levels (-0.6, 95 % CI: -1.2 to -0.05; P = 0.03) was also suggested. Higher baseline RANK-L protein levels were associated with a significantly lower response rate, but only in the synbiotic group (OR: 0.1, 95 % CI: -4.3 to - 0.3, P = 0.02). In the placebo group, higher IL-17A levels at baseline were significantly associated with a higher improvement in in particular, emotional dysregulation (P = 0.04), opening a door for new (targeted) drug intervention. However, larger prospective studies are warranted to confirm the findings. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03495375.

Are Genetic and Environmental Risk Factors for Psychopathology Amplified in Children with Below-Average Intelligence? A Population-Based Twin Study.

There is a negative association between intelligence and psychopathology. We analyzed data on intelligence and psychopathology to assess this association in seven-year-old Dutch twin pairs (ranging from 616 to 14,150 depending on the phenotype) and estimated the degree to which genetic and environmental factors common to intelligence and psychopathology explain the association. Secondly, we examined whether genetic and environmental effects on psychopathology are moderated by intelligence. We found that intelligence, as assessed by psychometric IQ tests, correlated negatively with childhood psychopathology, as assessed by the DSM-oriented scales of the Child Behavior Check List (CBCL). The correlations ranged between - .09 and - .15 and were mainly explained by common genetic factors. Intelligence moderated genetic and environmental effects on anxiety and negative affect, but not those on ADHD, ODD, and autism. The heritability of anxiety and negative affect was greatest in individuals with below-average intelligence. We discuss mechanisms through which this effect could arise, and we end with some recommendations for future research.

Inflammatory biotype of ADHD is linked to chronic stress: a data-driven analysis of the inflammatory proteome.

The association between Attention Deficit Hyperactivity Disorder (ADHD) and low-grade inflammation has been explored in children but rarely in adults. Inflammation is characteristic of some, but not all, patients with ADHD and might be influenced by ADHD medication but also lifestyle factors including nutrition, smoking, and stress. It is also still unclear if any specific symptoms are related to inflammation. Therefore, we assessed 96 inflammatory proteins in a deeply phenotyped cohort of 126 adult ADHD participants with a stable medication status using OLINK technology. A data-based, unsupervised hierarchical clustering method could identify two distinct biotypes within the 126 ADHD participants based on their inflammatory profile: a higher inflammatory potential (HIP) and a lower inflammatory protein potential (LIP) group. Biological processes that differed strongest between groups were related to the NF-κB pathway, chemokine signaling, IL-17 signaling, metabolic alterations, and chemokine attraction. A comparison of sample characteristics revealed that the HIP group was more likely to have higher levels of chronic stress (p < 0.001), a higher clinical global impression scale score (p = 0.030), and a higher risk for suicide (p = 0.032). Medication status did not influence protein levels significantly (p ≥ 0.074), but psychotropic co-medication (p ≤ 0.009) did. In conclusion, our data suggest the presence of two distinct biotypes in adults with ADHD. Higher levels of inflammatory proteins in ADHD are linked to higher levels of chronic perceived stress in a linear fashion. Further research on inflammation in adults with ADHD should take stress levels into account.

Emotion dysregulation as cross-disorder trait in child psychiatry predicting quality of life and required treatment duration.

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.

The short and long-term effects of a lifestyle intervention in children with mental illnesses: a randomized controlled trial (Movementss study).

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 children with MI. TRIAL REGISTRATION: trialsearch.who.int/ NL9822. Registered at November 2nd, 2021.

Short-term effects of an elimination diet and healthy diet in children with attention-deficit/hyperactivity disorder: a randomized-controlled trial.

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 ).

Sex differences in the course of autistic and co-occurring psychopathological symptoms in adolescents with and without autism spectrum disorder.

LAY ABSTRACT: There 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 adolescents with milder forms of ASD to those in a group of the general population with an equal intelligence quotient (IQ) and socioeconomic status. Data of five assessment moments from ages 11 to 22 years were analyzed using a statistic procedure that allowed us to determine which factors affect the course of symptoms over time. We found that in adolescence, sex differences in the course of psychopathological symptoms specific for autism are confined to the repetitive stereotyped domains. Males had higher scores on the sensory/stereotypic and resistance to change domains, the latter difference disappeared during the course of adolescence due to an increase of these problems in autistic females. Other sex differences, among which an increase over time in mood and anxiety problems in females was the most outstanding, were also observed in females without autism. These sex-specific differences have relevance in the clinical care of autistic men and women, although they are subtle compared to differences between individuals with and without autism.

Commentary: Why treatment is the best choice for childhood mental disorders - a commentary on Roest et al. (2022).

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.

Toward Precision Medicine in ADHD.

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.

Characterizing the heterogeneous course of inattention and hyperactivity-impulsivity from childhood to young adulthood.

To advance understanding of the heterogeneity in the course of ADHD, joint symptom trajectories of inattention and hyperactivity-impulsivity from childhood to young adulthood were modelled and associated with genetic, demographic, and clinical characteristics. Data were obtained from the NeuroIMAGE cohort which includes 485 individuals with ADHD, their 665 siblings, and 399 typically developing children. Trajectories were based on scores of the Conners Parent Rating Scale Revised and estimated over seven homogeneous age bins (from 5 to 28 years) using parallel process latent class growth analysis on data collected across 2-4 time points. Multilevel multinomial logistic regression was used to identify characteristics that differentiated between the derived classes. A seven-class solution revealed "severe combined stable" (4.8%), "severe combined decreasing" (13%), "severe inattentive stable" (4.8%), "moderate combined increasing" (7.5%), "moderate combined decreasing" (12.7%), "stable mild" (12.9%), and "stable low" (44.3%) classes. Polygenic risk for depression, ADHD diagnosis, ADHD medication use, IQ, comorbid symptom levels (foremost oppositional behaviour), and functional impairment levels differentiated classes with similar ADHD symptom levels in childhood but a diverging course thereafter. The course of ADHD is highly heterogeneous, with stable, decreasing, and increasing trajectories. Overall, severe symptom levels in childhood are associated with elevated-to-severe symptom levels in adolescence and young adulthood, despite substantial symptom reductions. Beyond symptom severity in childhood, genetic, demographic, and clinical characteristics distinguish the heterogeneous course.

Correction: Szopinska-Tokov et al. Investigating the Gut Microbiota Composition of Individuals with Attention-Deficit/Hyperactivity Disorder and Association with Symptoms. Microorganisms 2020, 8, 406.

The authors wish to make the following correction to this paper [...].

Longitudinal Associations Between Symptoms of ADHD and BMI From Late Childhood to Early Adulthood.

BACKGROUND AND OBJECTIVES: Attention-deficit/hyperactivity disorder (ADHD) and obesity are 2 frequent conditions that co-occur, which has implications for the management of both conditions. We hypothesized that ADHD symptoms predict BMI and vice versa from late childhood (10-12 years) up to early adulthood (20-22 years). METHODS: Participants were adolescents in the Netherlands (n = 2773, 52.5% male, mean age = 11 years at baseline, 5 waves up to mean age 22) from the Tracking Adolescents' Individual Lives Survey cohort. We examined bidirectional relationship between ADHD symptoms (hyperactivity/impulsivity and inattention) and BMI using the random intercept cross-lagged panel model. Time-varying covariates were pubertal status, stimulant use, depressive symptoms, and family functioning, and socioeconomic status was a time-invariant covariate. RESULTS: We found a time-invariant association of BMI with hyperactivity and impulsivity, but not with inattention, which was slightly stronger in female adolescents (female: r = 0.102; male: r = 0.086, P < .05). No longitudinal direct effects were found between ADHD symptoms and BMI during this period. CONCLUSIONS: Over the course of adolescence, the link between ADHD and BMI is stable and is predominantly with hyperactive and impulsive symptoms rather than inattention. There was no direct effect of ADHD symptoms on BMI increase nor of BMI on enhanced ADHD symptoms during this developmental period. The findings point to a shared genetic or familial background and/or potential causal effects established already earlier in childhood, thus suggesting that intervention and prevention programs targeting overweight and obesity in children with ADHD should be implemented in early childhood.

Neurocognitive markers of late-onset ADHD: a 6-year longitudinal study.

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.

A polygenic risk score analysis of ASD and ADHD across emotion recognition subtypes.

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.

Involvement of the 14-3-3 Gene Family in Autism Spectrum Disorder and Schizophrenia: Genetics, Transcriptomics and Functional Analyses.

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.

A two arm randomized controlled trial comparing the short and long term effects of an elimination diet and a healthy diet in children with ADHD (TRACE study). Rationale, study design and methods.

BACKGROUND: Food may trigger Attention-Deficit/Hyperactivity Disorder (ADHD) symptoms. Therefore, an elimination diet (ED) might be an effective treatment for children with ADHD. However, earlier studies were criticized for the nature of the control group, potential confounders explaining the observed effects, unsatisfactory blinding, potential risks of nutritional deficiencies and unknown long term and cost-effectiveness. To address these issues, this paper describes the rationale, study design and methods of an ongoing two arm randomized controlled trial (RCT) comparing the short (5 week) and long term (1 year) effects of an elimination diet and a healthy diet compared with care as usual (CAU) in children with ADHD. METHODS: A total of N = 162 children (5-12 years) with ADHD will be randomized to either an ED or a healthy diet. A comparator arm including N = 60 children being solely treated with CAU (e.g. medication) is used to compare the effects found in both dietary groups. The two armed RCT is performed in two youth psychiatry centers in the Netherlands, with randomization within each participating center. The primary outcome measure is response to treatment defined as a ≥ 30% reduction on an ADHD DSM-5 rating scale (SWAN) and/or on an emotion dysregulation rating scale (SDQ: dysregulation profile). This is assessed after 5 weeks of dietary treatment, after which participants continue the diet or not. Secondary outcome measures include the Disruptive Behavior Diagnostic Observational Schedule (DB-DOS), parent and teacher ratings of comorbid symptoms, cognitive assessment (e.g. executive functions), school functioning, physical measurements (e.g. weight), motor activity, sleep pattern, food consumption, nutritional quality of the diet, adherence, parental wellbeing, use of health care resources and cost-effectiveness. Assessments take place at the start of the study (T0), after five weeks (T1), four months (T2), eight months (T3) and 12 months of treatment (T4). T0, T1 and T4 assessments take place at one of the psychiatric centers. T2 and T3 assessments consist of filling out online questionnaires by the parents only. DISCUSSION: This RCT will likely contribute significantly to clinical practice for ADHD by offering insight into the feasibility, nutritional quality, (cost-)effectiveness and long term effects of dietary treatments for ADHD. TRIAL REGISTRATION: www.trialregister.nl, NTR5434. Registered at October 11th, 2015.

Investigating the Gut Microbiota Composition of Individuals with Attention-Deficit/Hyperactivity Disorder and Association with Symptoms.

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.