Attention deficit hyperactivity disorder (ADHD), obsessive compulsive disorder (OCD) and tic disorders (TD) commonly co-occur. In addition, specific inattention difficulties and poor impulse control are related to TD in the absence of comorbid ADHD. In this study we reanalyzed data from a recently completed study comparing internet-delivered, self-help comprehensive behavioral intervention for tics (ICBIT) with a waiting-list control group. The current study describes the effects of an (ICBIT) in children and adolescents with TD with and without comorbid diagnoses of ADHD or OCD at post intervention and over three- and six-month follow-up periods. Thirty-eight 7 to 18-year-olds completed the ICBIT. Of these, 16 were diagnosed with comorbid ADHD and 11 were diagnosed with OCD. A significant improvement in tic measures was found in all groups. Both the TD + ADHD and the TD − ADHD groups were similar in the magnitude of tic reduction from baseline to post-treatment, and at the three and six-month follow-up assessments. However, the TD + OCD group benefitted less from intervention than the TD—OCD group. There were meaningful reductions in parental reports of inattention, as well as hyperactive and impulsive symptoms at post intervention and over the 6-month follow-up period. Thus, ICBIT can be effectively delivered in the presence of comorbid ADHD or OCD symptomatology and may reduce symptoms of inattention and impulsivity. Larger studies of ICBIT in children and teens with TD and comorbid ADHD and OCD are needed to optimize responses to ICBIT. Tourette syndrome (TS) and chronic tic disorder (CTD) (collectively referred to as tic disorders TD) are neurodevelopmental disorders characterized by sudden, rapid, recurrent motor movements or vocalizations that persist for more than a year . TS is dPeople with TD, including children and adolescents, are able to suppress their tics for variable periods of time but frequently experience premonitory urges, which are defined as unpleasant and distressing sensory phenomena or perceived need to move that often increase before tics and during tic suppression. These premonitory urges are often momentarily relieved by the expression of the tic. The core therapeutic techniques of habit reversal training (HRT) and its expansion comprehensive behavioral intervention for tics (CBIT) for people with TD are forms of interoceptive awareness training and tic suppression that harness a competitive response based on this suppressibility. These interventions eventually lead to decreased tic frequency and severity ,6.Of all the comorbid disorders associated with TD, attention-deficit/hyperactivity disorder (ADHD) and obsessive compulsive disorder (OCD) and subclinical obsessive compulsive behavior (OCB) are the most common . ADHD isTics are believed to be related to impaired inhibition of associative and motor cortico-striato-thalamo-cortical circuits . People Studies have indicated that comorbid ADHD places a greater burden on response inhibition in children and teens with TD than do tics, and contributes the most to the increased incidence of school problems, social difficulties, and the presence of other emotional disorders ,14. HoweThese studies suggest that the significant impaired inhibitory performance and increased neural activity deficits in ADHD may impede patients’ ability to suppress tics and engage in therapy, thereby reducing the effect of behavioral treatments that target tics specifically.Studies on tic suppressibility and behavioral treatment for patients with TD and co-occurring ADHD are inconclusive. Several studies have shown that individuals with comorbid TD and ADHD benefitted less from behavioral treatment than children and teens with TD without ADHD ,18. SambOCD is characterized by the presence of obsessions, compulsions or both that cause clinically significant distress or impairment in functioning . OCD wasStudies by Sukhodolsky et al. , and McGAlthough a substantial proportion of children and teens with TD have comorbid ADHD or OCD, there are only a few studies on the differential effects of behavioral treatment in this population with comorbid ADHD or OCD or studies on the effects of behavioral treatment on specific attentional and impulse control difficulties in children and teens with TD without ADHD.Comprehensive behavioral intervention for tics (CBIT)  has gainThus, the current study aimed to assess the following: (1) whether ICBIT elicits a differential response in children and teens with comorbid ADHD compared to those with TD without ADHD; (2) the efficacy of ICBIT on specific difficulties of inattention and impulse control that are related to TD for the entire cohort; (3) whether ICBIT would elicit a differential response in children and teens with comorbid OCD compared to children and teens with TD without comorbid OCD.n = 38) [Data from the ICBIT trial (n = 38)  were usen = 38) . This trn = 38) . The incn = 38) , a Yale n = 38)  of mild M = 11.29, SD = 1.97) with a principal diagnosis of TS (n = 29) or CTD (n = 9). Of these, n = 16 met the DSM-5 criteria for ADHD [n = 11 met the DSM-5 criteria for OCD [An intention-to-treat principle was applied. Assessments were at baseline, post-ICBIT, 3 and 6 months post-ICBIT completion. After obtaining informed consent, eligible participants were invited to complete an online clinical assessment. Online clinical interviews were based on the Anxiety Disorders Interview Schedule, the ADIS-C/P . The samfor ADHD  and n =  for OCD .The outcomes were measured at baseline, post-intervention, and at 3 months and 6 months after randomization, and were administered by independent masked clinicians at baseline, post-intervention and at the 3- and 6-month follow-up assessments.The primary outcomes were tic severity as measured by the YGTSS , a cliniParents and children reported secondary outcomes online. These included The Revised Connors’ Parent Rating Scale, the CPRS-R  which waOCB severity was measured through the Obsessive Compulsive Inventory; OCI-CV , a 21-itThe ICBIT program consists of 9 consecutive conjoint child-caregiver modules, delivered over 9 weeks. ICBIT facilitates self-help therapy through age-appropriate texts and descriptive diagrams, animations, and video clips of clinicians demonstrating techniques. Module 1 presents psychoeducational information about tics and awareness training for tic occurrence. Module 2 covers stress management skills. Module 3 presents a function-based environmental intervention. Module 4 presents information about a competing response and how to identify the premonitory urge for the first tic. In module 5–7 the participants and their parents continue training for the second, third, fourth and the fifth tics. In module 8 the participants and their parents continue training for the sixth tic and generalization training. The patients practice various daily situations including more challenging scenarios that can exacerbate tics. Module 9 comprises skills, methods and instructions for further practice aiming at maintaining intervention gains and relapse prevention. This module was repeated once a month as a monthly booster module for the next 6 months.n =16) or TD − ADHD (n = 22), TD + OCD (n =11) or TD − OCD (n = 27) with t tests for continuous variables and χ2 tests for categorical variables. Descriptive statistics were computed for demographic and clinical characteristics for the entire cohort and for each group. Differences between the groups were assessed using linear mixed effects model analyses to account for the correlations in the repeated measurements. In all linear mixed models, the comorbid condition, time, and the interaction between time and comorbid condition were added in the specification of the fixed effects. Data analyses were performed using SPSS, version 25.0 . Bonferroni corrections also were applied in post hoc comparisons of marginal means. Statistical significance for all analyses was set at p < 0.05 for a two-tailed test.Baseline characteristics were compared between groups, TD + ADHD (n = 16) consisted of significantly more males than females compared to The TD − ADHD group (n = 22). The TD + ADHD group (n = 16) presented with more learning disabilities and social phobia disorders, and higher ADHD symptom severity as measured by the CPRS-R. The CGAS scores in the TD + ADHD group were significantly lower, suggesting that ADHD leads to greater disability than TD alone. Apart from these, no differences were found in the demographic variables  F = 0.96, p = 0.42, and severity of vocal tics (YGTSS VTS) F = 0.65, p = 0.58, and impairment scores (YGTSS IS) F = 1.62, p = 0.20  0.20 see .2(4) = 4.31, p = 0.36The improvement rate for tics (as indicated by a score of 1 and 2 on the CGI-I) was significant in both groups. At Time 2 in the TD + ADHD group 50% (8/16) improved significantly, while in the TD − ADHD group 68.18% (15/22) improved significantly. At Time 3, in the TD + ADHD group 81.25% (13/16) improved significantly while in the TD − ADHD group 72.72% (16/22) improved significantly. At Time 4, in the TD + ADHD group 87.50% (14/16) improved significantly while in the TD − ADHD group 95.45% (21/22) improved significantly, χF = 0.50, p = 0.68 , no significant differences were found between the groups in improving attention and concentration symptoms; n = 16), the improvement rate for ADHD was not significant , there was a significant improvement on the CPRS-R total score F = 12.77, p < 0.00, as well as significant improvements on the inattentive F = 4.32, p < 0.01, hyperactivity-impulsivity F = 13.31, p < 0.00, anxiety F = 10.33, p < 0.00, and psychosomatic F = 5.88, p < 0.00, subscales from baseline to post-treatment, as well as in the 3- and 6-month follow-up assessments. However, no significant effect was found on the behavioral problems sub-scale; F = 3.49, p = 0.20.For the whole sample (n = 38), there was a significant improvement on the OCI-CV total score, F = 11.07, p < 0.00.For the whole sample (n = 11) and TD − OCD group (n = 27) for the demographic variables  = 13.30, p = 0.10 (see The improvement rate for tic severity (as indicated by a score of 1 and 2 on the CGI-I) was significant in both groups. At Time 2, in the TD + OCD group , TD − OCD group , At Time 3, in the TD + OCD group , TD − OCD group , At Time 4, in the TD + OCD group , TD − OCD group , χ0.10 see .n = 11), the improvement rate on CGI-I for OCD was not significant (see For those participants who were diagnosed with OCD at Time 1 (cant see .n = 4), TD + ADHD − OCD (n = 12), TD − ADHD + OCD (n = 7) and TD − ADHD − OCD (n = 15).This study consisted of a small sample size. Therefore, we were underpowered to adequately compare changes in terms of tic severity in children and teens with TD and specific comorbidities that may moderate outcomes following ICBIT, relative to children and teens without such specific comorbidities. However, to further explore treatment response in terms of comorbidity, we further classified the participants into the following 4 groups: TD + ADHD + OCD . These findings suggest that the tic reduction may lessen the burden placed by tics on attentional resources  and therHigh rates of comorbid obsessive compulsive symptoms were reported in children and teens with TD . FurtherOverall, the results of the current study indicate that ICBIT may be effective for children and teens with TD and ADHD. However, the results show that an OCD comorbid condition may attenuate treatment outcomes. Despite the fact that the majority of children and teens with TD experience clinically significant reduction in TD symptoms following behavioral treatment, the effectiveness of the treatment is not sufficient to relieve all the tic symptoms . As was The use of the internet as a therapeutic platform can provide a safe and effective alternative solution to dealing with accessibility problems. The outbreak of the COVID-19 pandemic has posed many new challenges to traditional face-to-face therapy. ICBIT may become a standard method for the dissemination of evidence-based therapy for children and teens with TD and comorbid ADHD and OCD.However, the results should be considered in light of the limitations of this study, which consisted of a small sample. Further, since children and teens with ADHD or OCD who required immediate treatment were not included, it is likely that severe ADHD or OCD may further complicate interventions targeting tics . The posAssessing the effect of comorbid disorders on ICBIT is the first step toward enhancing the ability of children and teens with TD to adhere to required treatment assignments that are likely to positively affect treatment gains. The current findings suggest that tics, OCD and ADHD symptoms should be carefully assessed and be the target of behavioral interventions in young people with TD.Therapy for TD with comorbid OCD, OCB or ADHD should be tailored to individual difficulties and needs, with various modalities that focus on tics and comorbid symptoms. These interventions can include adaptations to young people with ADHD, such as immediate rewards, and allowing for more frequent breaks to encourage the child’s motivation and regulation ,25,26,37


ASD and ADHD are prevalent neurodevelopmental disorders that frequently co-occur and have strong evidence for a degree of shared genetic aetiology. Behavioural and neurocognitive heterogeneity in ASD and ADHD has hampered attempts to map the underlying genetics and neurobiology, predict intervention response, and improve diagnostic accuracy. Moving away from categorical conceptualisations of psychopathology to a dimensional approach is anticipated to facilitate discovery of data-driven clusters and enhance our understanding of the neurobiological and genetic aetiology of these conditions. The Monash Autism-ADHD genetics and neurodevelopment (MAGNET) project is one of the first large-scale, family-based studies to take a truly transdiagnostic approach to ASD and ADHD. Using a comprehensive phenotyping protocol capturing dimensional traits central to ASD and ADHD, the MAGNET project aims to identify data-driven clusters across ADHD-ASD spectra using deep phenotyping of symptoms and behaviours; investigate the degree of familiality for different dimensional ASD-ADHD phenotypes and clusters; and map the neurocognitive, brain imaging, and genetic correlates of these data-driven symptom-based clusters.The MAGNET project will recruit 1,200 families with children who are either typically developing, or who display elevated ASD, ADHD, or ASD-ADHD traits, in addition to affected and unaffected biological siblings of probands, and parents. All children will be comprehensively phenotyped for behavioural symptoms, comorbidities, neurocognitive and neuroimaging traits and genetics.The MAGNET project will be the first large-scale family study to take a transdiagnostic approach to ASD-ADHD, utilising deep phenotyping across behavioural, neurocognitive, brain imaging and genetic measures.The online version contains supplementary material available at 10.1186/s13229-021-00457-3. Autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD) are neurodevelopmental disorders affecting 1–2% and 5% of the population, respectively , 220. ASAlthough ASD and ADHD are diagnosed according to a symptomatic and behavioural presentation and developmental history, both conditions have a strong genetic aetiology and are highly heritable with estimates of up to 85% for ASD  and 70–9Copy number variations CNV’s; , 290), d, d290]),Traditional taxonomies, such as the DSM and ICD, inherently assume segmentation between diagnostic categories. However, high rates of comorbidity between specific disorders, for example ASD and ADHD with intellectual disability ID; , 278, obThe principal focus of RDoC is the analysis of dimensional phenomena at multiple levels of analysis across several core functional domains. These include behaviour, cognition, neural circuits, and genes in areas such as social processes and cognitive systems. These elements are organised within the RDoC matrix, which is primarily intended as a heuristic framework to encourage and facilitate psychiatric research that is unconstrained by traditional diagnostic categories. The primary focus of HiTOP is the articulation of the structure of the symptoms of psychopathology, which are conceptualised as hierarchically organised dimensions , 163. Thsustained attention and arousal ). arousal , 289, coon e.g. , 301), s, ssustai of mind , 281, vig memory , 227, ann-making , 309. Sewith ASD , 194, wiwith ASD . These awith ASD , 199.p’ factor, represented at the top of the hierarchy and reflecting a common liability for mental disorder [p’ factor are super spectra; internalising, externalising, and psychosis; representing shared vulnerabilities to more specific ranges of problems. Internalising symptoms encompass depression, anxiety and somatic, eating and sexual difficulties, and subsumes the narrower and distinct subspectra of fear and distress. The externalising domain subsumes substance abuse and antisocial behaviours and is further differentiated into the disinhibited externalising (e.g. impulse-control problems) and antagonistic externalising  subspectra. The psychosis super-spectra captures phenotypic variance related to psychotic disorders, but can be further differentiated into thought disorder  and detachment .Although dimensional models of psychopathology originated in the developmental literature , 139, nedisorder , 66. Belp factor, externalizing and internalizing superspectra [To date, the full HiTOP model is more clearly articulated in adult populations , 163 andrspectra , 265). Drspectra . An advarspectra . If neurrspectra , and socrspectra  subfactoMAGNET is uniquely positioned to examine the relationship of ADHD and ASD to other forms of psychopathology within a hierarchical dimensional model, because phenotypes related to these conditions are being measured at a finer level of granularity compared to previous studies , 228. FoA conceptual cross-mapping between RDoC and HiTOP has previously been outlined , 188. HiThe MAGNET study addresses several limitations of existing research. First, by incorporating multiple measures of ADHD and ASD symptomatology within the same structural modelling study, along with measures of other HiTOP spectra and subspectra , we are in a position to investigate the placement of these neurodevelopmental conditions, their potential subdimensions and/or subtypes, within a broader structural model of child psychopathology . Second, our methodology includes an array of measures that align with the constructs and subconstructs included in the RDoC matrix and across multiple levels of analysis, including behavioural assessment, cognitive paradigms, and genes. This uniquely positions the MAGNET study to address multiple potential points of convergence at the RDoC-HiTOP interface, as well as utilize the biologically-informed constructs of RDoC to test the validity of any ADHD/ASD phenotypic subdimensions or clusters. Of particular relevance is the cross-mapping of HiTOP dimensions and the RDoC Sensorimotor Process construct, for which there is currently no evidence . The MAGCurrent studies attempting to uncover the neurobiological correlates of ASD and ADHD typically take one of two approaches. The first approach aims to recruit large sample sizes to facilitate high powered genetic analyses, with the trade-off being that only surface level phenotyping of behaviour is typically captured . The secThere is increasing momentum toward transdiagnostic research efforts, as evidenced through projects such as the NIMH-funded Bipolar Schizophrenia Network on Intermediate Phenotypes (B- SNIP) project , which aAlthough there is consistent evidence suggesting shared genetic liability and family aggregation for ASD and ADHD, direct evidence for shared DNA variation from techniques such as GWAS or DNA has been harder to discern , 242. OnTo our knowledge there is no current study taking a truly transdiagnostic approach to understand the symptomatic, neurobiological (neurocognitive and neuroimaging) and genetic overlap between ASD and ADHD. A transdiagnostic sampling strategy that combines a family study design with deep dimensional phenotyping is needed across the ASD-ADHD spectra. By drawing on both RDoC and HiTOP frameworks, the MAGNET Project will contribute to our understanding of how neurodevelopmental disorders fit into a data-driven hierarchical taxonomy. Further, by understanding how these dimensional phenotypes present in families of children with ASD and ADHD, and whether siblings share similar behavioural signatures will provide crucial evidence for familiality of different ASD-ADHD phenotypes. The MAGNET Project therefore aims to: (1) identify data-driven symptom clusters across ADHD-ASD spectra using deep phenotyping of symptoms and behaviours; (2) investigate the degree of familiality for these data-driven symptom clusters; (3) map the neurocognitive and brain imaging correlates of these data-driven symptom clusters; and (4) explore their genetic correlates.internalising and externalising symptoms, attention and cognitive control, arousal, reward, working memory, perception, social processes, and sensorimotor processes). The battery uniquely captures dimensional traits across ASD-ADHD spectra using a range of symptom, parent-report, neurocognitive, and direct behavioural observation measures to capture the target domains from multiple perspectives. This approach will provide a rich source of data unconfounded by informant bias and method bias, with the opportunity to model the correspondence and complex interactions of information obtained from multiple informants [The MAGNET Project will enrol 1200 families with children aged between 4 and 18 years of age. Children who are typically developing, as well as those with a diagnosis of ASD, ADHD, or ASD + ADHD will be recruited to ensure both ends of the ASD-ADHD spectra are appropriately sampled. Children who are under investigation for ASD and/or ADHD and are referred to the study by their paediatrician will also be recruited. In addition, unaffected and affected siblings of probands will be recruited. A dimensional enhancement approach to sampling will be taken, as it augments clinical samples with non-clinical participants and those exhibiting subthreshold symptoms , 161. Thformants , 219.Targeted sampling through hospitals, schools, private practice clinicians, and social media across Victoria, Australia will allow for a broad and representative distribution of socioeconomic status (SES) and symptom presentation. Currently the MAGNET Project is in an open recruitment phase. The MAGNET Project will actively recruit females and children with mild-severe intellectual disability, as these children are typically under-represented, or excluded from, studies of ASD and ADHD. The study has been piloted on control and clinical children aged 4 to 18 years of age  currently managing their care. Siblings of probands must share two biological parents with the proband. The healthy control children are required to have no neurodevelopmental diagnosis, no first-degree relative with a diagnosis of ASD and/or ADHD, and no history of a psychiatric (e.g. depression or anxiety) or neurological illness (e.g. head injury or tuberous sclerosis).Probands and siblings with comorbidities such as anxiety, depression, oppositional defiant disorder (ODD), conduct disorder (CD), and obsessive–compulsive disorder (OCD) are not excluded. As a large proportion of children with ASD and ADHD experience these comorbid disorders , 306, exAll children undergo case review by a registered psychologist and paediatrician, and speech pathologist if available, to determine a ‘best clinical estimate’ of that child’s current diagnostic status. A best clinical estimate will be given for ASD, ADHD, comorbid ASD/ADHD, intellectual disability (ID), CD, and ODD  may vary between ethnic populations and potentially cause false positive results in genetic association studies. To avoid the potential impact of population stratification only children with four grandparents of European ancestry are invited to complete the genetic component of the protocol.Only full biological siblings will be eligible to take part in the study. Within simplex families, that is, families where only one child has an ASD and/or ADHD diagnosis, the child with the ASD/ADHD diagnosis is nominated as the proband. In multiplex families, families where more than one child has an ASD and/or ADHD diagnosis, the eldest child is denoted as the proband and younger children are designated as affected or unaffected siblings. Unaffected siblings of ASD/ADHD probands have no diagnosis of ASD/ADHD, are not under investigation for ASD/ADHD, and are not assigned a neurodevelopmental disorder diagnostic category during their best clinical estimate review.The child’s current and previous medication history, medication prescriber , and reasons for any medication changes, will be recorded.Children who are taking medication remain on their medication during Visit 2 when their relevant Wechsler and Autism Diagnostic Observation Schedule—Second Edition (ADOS-2) assessments are completed  study team , 178. ThDimensional ASD symptomatology is measured through parent-report measures capturing social communication  and quaLanguage profiles in ASD are heterogeneous, ranging from non-verbal  to superA standardised screening measure for language difficulties  is admiThe Preschool Language Scale—Fifth Edition  is admisustained attention, inhibition, cognitive control, arousal, reward, working memory, perception, social processes, and sensorimotor processes with the view to utilise neurocognitive data to discover neurobiological correlates of novel ASD-ADHD data-driven clusters. The tasks chosen are widely used, have biological plausibility and show robust effects sizes when differentiating clinical cases from controls. See Table We assess the domains of The neurocognitive tasks will be completed on a desktop computer and touchscreen laptops. Amsterdam Neuropsychological Tasks (ANT), Psytools, PsychoPy and STOP-IT software programmes were used for task administration , 283.Response inhibition refers to the ability to withhold or cancel a motor response . SustainArousal can be understood as an individual’s state of reactivity, and although arousal is intimately linked with constructs like attention, the neural correlates of these processes are largely distinct . ArousalReward sensitivity refers to the tendency to respond more strongly to incentives, or rewards, and is a process implicated in decision making. ADHD is associated with divergent decision making, differing sensitivity to reward, and elevated risk-taking behaviour [ehaviour , 309. Efehaviour . Alteredehaviour . Childreehaviour , 276. Biehaviour , 94 and ehaviour ). DopamiIn ASD, there is evidence for aberrant reward processing, but to a lesser extent than that observed in ADHD , 277. ChTo assess decision making, reward sensitivity, and risk-taking, the New Cambridge Gambling Task  will be Broadly, cognitive flexibility is a component of executive function that encompasses adaptability at a behavioural level and is studied from a variety of perspectives such as set shifting, task-switching, and reversal learning . More spInternationally, the definitions of working memory are contentious, with working memory and short-term memory sometimes still used interchangeably. Some conceptualise working memory as the process of holding information in the mind for a short period of time, which can also be thought of as short-term memory . Others Emotion recognition is the ability to correctly identify another person’s emotion based on their facial expression and is crucial for effective social communication. Emotion recognition difficulties in children with ASD are a consistent and robustly replicated finding [ finding , 281. At finding , 206. Al finding , 84, 287 finding ; Karolin finding ).Theory of Mind (ToM) is the ability to understand and attribute mental states to oneself and to others and understand that others can have different mental states to yourself. Profound difficulties with understanding others’ thoughts and intentions in day-to-day life are common in ASD [n in ASD . These dn in ASD . False-bn in ASD . These dn in ASD . The abin in ASD .Saccade and pursuit eye movement abnormalities have the potential to reliably distinguish ASD and ADHD children from controls . OculomoLarge-scale neuroimaging studies have identified robust structural differences associated with ASD and ADHD, demonstrating both common and disorder-specific brain alterations. In both ASD and ADHD, cases showed reduced subcortical volumes , 235 andStructural and functional brain imaging (resting state fMRI) will be collected to determine if neurobiological differences exist as a function of symptom-based data-driven clusters. All scans will be performed using Siemens Skyra 3 T scanner following previously established protocols , 237. DaSaliva is collected from all probands, affected and unaffected biological siblings, biological parents of probands, and healthy controls for DNA extraction  study . GenotypA combination of supervised psychometric analyses and unsupervised clustering approaches will be used to converge on data-driven homogeneous ASD-ADHD clusters embedded within biologically-relevant dimensions based on previously derived factor score estimates , 106. ByDimension reduction strategies, such as exploratory factor analysis and exploratory structural equation modelling , 71, 182Factor mixture modelling is one possible supervised clustering method that we will employ for our subtyping analyses. Factor mixture modelling can uncover homogeneous clusters within continuous and categorical data embedded within dimensional models of psychopathology by utilising probabilistic modelling techniques , 189. ThThe MAGNET Project has completed initial piloting of the study protocol and entered into an open recruitment phase. It is the first large-scale study using a family design to take a truly transdiagnostic approach to ASD and ADHD that aligns with the principles of the RDoC matrix and HiTOP model of psychopathology.A significant amount of time is required in the conceptualisation of an assessment battery that is appropriate for the large range of cognitive abilities and ages, while adequately capturing dimensional ASD and ADHD traits. As a number of the measures included in the protocol were not initially intended for use across broad age ranges or levels of cognitive ability, it is important to allow for extra time during piloting to determine the minimum age and cognitive level for tasks with novel applications. Although such an approach required more time initially, it will translate into a high-quality dataset upon project completion.all children who participate in the MAGNET Project complete an ADOS-2. The ADOS-2 research training dictates coding of observed behaviours with no clinical interpretation to ensure research-reliable coding. Differentiating the social difficulties of children with ADHD on the ADOS-2 can be challenging, which has also been previously noted by Grzadzinski et al. [One of the measures used to confirm an ASD diagnosis, the ADOS-2, was chosen as it is internationally recognised as part of gold standard assessment. Uniquely, i et al. . ADOS daThe inclusion of children with ID will facilitate a sample that is largely representative of our target population, specifically within ASD. However, recruitment uptake for families of children with ID has been slow. These families often have children with high treatment needs which can be time consuming, in turn reducing the likelihood of these parents enrolling in a time-intensive research protocol. An alternative targeted recruitment strategy for these families will be needed moving forward, including direct communication with specialist school settings to engage teaching staff in the recruitment process for their learning community. Partnering with community grant funds and the Australian National Disability Insurance Scheme (NDIS) are further strategies the MAGNET team intends to utilise for recruitment of these children.As ASD and ADHD are highly heritable, with evidence for shared genetic liability in families, this inherently limits the number of possible unaffected siblings. A large number of families with children with ASD and/or ADHD will therefore be required to achieve sufficient numbers of unaffected siblings for high powered statistical analysis.A number of the large-scale biobanking projects and multi-site studies can experience significant missingness in their data. Protecting against missing data has been a key priority in the MAGNET Project protocol development. Initial piloting highlighted that ensuring parents completed all online questionnaires before attending the in-person research visits reduced missing data, and increased attendance rates to research visits. Comprehensive data collection at the initial point of contact with families will also allow us to determine if attrition and resulting missingness is attributed to characteristics of the family or child, thus allowing us to model the missingness and avoid bias in our results. With the oversight from the project’s supervising psychologist, families are provided with a results summary after participating, including outcomes from cognitive assessments, language assessments (where applicable), ASD and ADHD symptom scales, and ADOS-2 ratings. To increase retention rates between the first and second research visit for each family, the neurocognitive tasks are completed in the first research visit and the cognitive assessment and ADOS-2 are completed in the second. Importantly, other measures used in the best clinical estimate review, such as the DAWBA, are completed prior to participants first research visit. Saliva collection from all members of the family pedigree has also been challenging, especially from fathers. Currently we have noted that mothers will primarily bring children to their research visits. Good follow-up and regular contact with the family is imperative in ensuring the least amount of missing genetic data. Minimal manual handling of data with automatic backups of all clinical, neurocognitive, and oculomotor data reduces the risk of missing data through technical or human error. Sophisticated analysis strategies to manage missingness will be utilised by the MAGNET Project that accommodates some missing data under assumptions of Missing Completely At Random, or Missing At Random, such as multiple imputation, auxiliary variables, and expectations-maximisation algorithm , 123.The diversity of clinical specialists on the MAGNET Project team, including psychologists, cognitive neuroscientists, paediatricians, psychiatrists, and speech pathologists, is relatively unique. When research teams are large, this increases potential variability in administration of assessments, and thus variability in data quality. The MAGNET Project team undergo regular and ongoing staff training and clinical supervision from the project’s supervising psychologist. As a result, all members are consistently building skills to maximise participant engagement and data-capture across all tasks and assessments.It is possible that the MAGNET Project’s sampling strategy will not achieve a true community sample upon completion. However, a variety of recruitment avenues and methods will be utilised to achieve a sample with breadth in symptomatology and phenotype. The project will provide insight into ASD and ADHD’s place within a hierarchical taxonomy of psychopathology and neurodevelopment. Although the study primarily targets traits central to these disorders, the full breadth of neurodevelopmental difficulties and common comorbidities (e.g. anxiety) are not captured with the same degree of granularity. The MAGNET Project will therefore provide one piece of the much larger puzzle in the quest for understanding neurodevelopment in a hierarchical framework. The broad range of cognitive abilities captured by the project, which allows a more representative sample, also means a proportion of children with more severe ID may not be able to complete all neurocognitive and/or imaging protocols. Nevertheless, our minimum dataset protocol is designed to provide minimal missing data across key tasks.Clinical heterogeneity and unitary conceptualisations of ASD and ADHD have hampered attempts to understand the structure of developmental psychopathology and associated neuropsychology, neurobiology and genetics. Current attempts to uncover the genetic aetiology of ASD/ADHD are limited with respect to one or more of the following: (1) recruitment is restricted to diagnostic categories that ignore the dimensional organisation of psychopathology symptoms, comorbidity, and within-group heterogeneity ; (2) minAdditional file 1. MAGNET Project study protocol summary.Additional file 2. Best clinical estimate protocol.Additional file 3. Protocol for testing non-verbal children and children with ID.Additional file 4. Clinical assessments protocol.Additional file 5. Research visit and neurocognitive testing protocol summary.Additional file 6. Oculomotor testing protocol.Additional file 7. Saliva collection protocol.


N = 6675 children . Regressions showed that less sedentary behavior at age 7 predicted more ADHD symptoms at age 14 . The result remained significant when controlled for ADHD symptoms at age 7, sex, BMI, month of birth, SES and ethnicity . ADHD diagnosis at age 14 was also significantly predicted by less sedentary behavior at age 7 (β  =  − 0.008). Our findings show that symptoms of ADHD can be predicted by objective activity data 5 years in advance and suggest that actigraphy could be a useful instrument aiding an ADHD diagnosis. Interestingly, the results indicate that the key difference between children with and without ADHD lies in reduced sedentary activity, i.e., times of rest.Hyperactivity is one of the three core symptoms in children with attention deficit hyperactivity disorder (ADHD). Diagnosing ADHD typically involves self-report, third party report and observations. Objective activity data can make a valuable contribution to the diagnostic process. Small actigraphy studies in clinical samples have shown that children with ADHD move more than children without ADHD. However, differences in physical activity between children with and without ADHD have not been assessed in large community samples or longitudinally. This study used data from the Millennium Cohort Study to test whether symptoms of ADHD (parent-rating Strengths and Difficulties Questionnaire) and ADHD diagnosis at age 14 (reported by parents) could be predicted from objective activity data (measured with actigraphs) at age 7 in The online version of this article (10.1007/s00787-020-01566-9) contains supplementary material, which is available to authorized users. Attention deficit hyperactivity disorder (ADHD) is a common childhood-onset, neurodevelopmental disorder that is characterized by three core symptom domains: hyperactivity, inattention and impulsivity . ADHD isTo diagnose ADHD, clinicians typically rely on observations and reports from several different sources, such as the parents, school reports and the report of the affected child or adult. However, one of the main limiting factors in reaching an ADHD diagnosis is limited, corroborating evidence from family and friends . NeuropsA few objective measures can be used to aid the diagnostic process and assess symptom domains in ADHD, such as continuous performance tests and actigraphy. Continuous performance tests can assess attention and impulsivity and could potentially aid a clinical diagnosis, although evidence is somewhat mixed . The useActigraphy is a non-invasive, objective measure of physical activity. Actigraphs are worn on the body and record motor activity. A number of smaller studies have found that children with ADHD have a higher activity level than controls –13, whilA line of studies has shown that increased activity level ratings in infancy positively predict ADHD symptoms in later childhood –22. StudMoreover, objective measures of ADHD indicators can be helpful in assessing outcomes for intervention, in addition to ratings. For instance, a study using actigraphy data showed no beneficial effect of a behavioral school program on objective activity levels, while the program was judged as successful by teacher ratings . A meta-Differences in physical activity between children with and without ADHD have only been assessed in relatively small, clinical samples, not community samples. The aim of this study was to assess whether objectively measured physical activity in childhood (at age 7) over 7 days can predict ADHD symptoms (continuous) and ADHD diagnosis in adolescence (at age 14) in a large, representative, longitudinal UK population-based cohort study , 28.https://cls.ucl.ac.uk/cls-studies/millennium-cohort-study/. Families were recruited via random sampling using all listed parents on the UK Child Benefit registers. [Participants are from the Millennium Cohort Study (MCS),  a UK birgisters.  The sampN = 6675 children, aged 7. Data for all four activity indices and SDQ ADHD data at ages 7 and 14 was available for N = 5251 children . The items for the subscale are ‘restless, overactive, cannot stay still for long’, ‘constantly fidgeting or squirming’, ‘easily distracted, concentration wanders’, ‘thinks things out before acting’, ‘sees tasks through to the end, good attention span’. Every item is rated on a three point Likert scale: ‘not true’ (0), ‘somewhat true’ (1) and ‘certainly true’ (2). Positively worded items are reverse-scored. The possible range is 0–10 .Activity was recorded using the Actigraph GT1M uni-axial-accelerometer  and the ActiLife Lifestyle Monitoring System software version 3.2.11 . Children were instructed to wear the accelerometer around the hip for seven consecutive days during waking hours. Sampling epochs were every 15 s; activity data and step count were recorded . Four vaR2 change. SDQ hyperactivity/inattention values at age 14 were predicted using linear regression with the four activity indicators as independent variables in model 1. Control predictors were entered gradually in consecutive models. In model 2, SDQ hyperactivity/inattention values at age 7 were entered as a control variable. Model 3 included sex, BMI at age 7 and 14, and month of birth , parental education across sweeps , parental income  as an indicator of SES and ethnicity in addition. Due to the small number of parents giving information on medication intake for ADHD, we ran a separate, smaller model, predicting SDQ hyperactivity/inattention values at age 14 from the four movement parameters and hyperactivity/inattention values at age 7 (supplementary Table 1). Weights generated to account for both the sampling design of the Millennium Cohort Study and the smaller sample with accelerometry data were used to weight all analysis to obtain nationally representative estimates in all analysis.Several linear regression models were conducted in SPSS and compared, using Because of the low base rate of ADHD diagnosis in the sample (1.6%), a rare events logistic regression was conducted in R with ADHD diagnosis at age 14 as a dependent variable and the 4 activity indicators and sex as the independent variables.R(5251) = 0.57, p < 0.001. Correlations between SDQ hyperactivity/inattention at age 7 and the four activity indicators revealed a significant negative association between hyperactivity and sedentary activity R(6371) =   − 0.12, p < 0.001, and positive associations between hyperactivity and light R(6371) = 0.12, p < 0.001, moderate R(6371) = 0.15, p < 0.001 and vigorous R(6371) = 0.10, p < 0.001.The mean rating for SDQ hyperactivity/inattention declined from age 7–14 (see Table N = 68) was associated with significantly less sedentary behavior t(6476) =  − 2.55, p = 0.011, d =  − 0.33; more light t(6476) 2.18, p = 0.029, d = 0.28, moderate t(6476) = 2.19, p = 0.029, d = 0.27 and vigorous activity t(6476) = 3.25, p = 0.001, d = 0.35.An ADHD diagnosis at age 7 , BMI and ethnicity. While childhood ADHD symptom severity as a relevant predictor for adulthood ADHD symptoms has been well established , 43, eviChildren of mixed and Asian ethnicity had lower parent-reported hyperactivity levels than white children. Several studies haves shown that nonwhite children were less likely to be diagnosed with ADHD than white children –54, wherInterestingly, a lower BMI at age 7 predicted hyperactivity/inattention at age 14, but a higher BMI at age 14 was associated with higher hyperactivity/inattention levels at age 14. ADHD has been associated with disordered eating (problematic eating behavior that does not meet diagnostic criteria) and eating disorders , 61. DisRegarding different activity levels at age 7, the data showed that children with an ADHD diagnosis were more active than children without an ADHD diagnosis. This is in line with previous studies , 65–67. A limitation of the current study is that common comorbidities that can affect activity levels, such as tics, could not be taken into account. Moreover, participants who had complete datasets had lower SDQ hyperactivity/inattention scores at age 7 and 14, lower moderate activity levels, and lower income. It is therefore possible that our analyses underestimate the association between hyperactivity/inattention and activity level.In conclusion, hyperactivity and ADHD diagnosis at age 14 can be significantly predicted by objective activity levels at age 7, particularly by lower sedentary activity levels. Measuring sedentary activity levels during waking hours could be further developed to aid in the early identification and diagnosing of ADHD.Supplementary file1 (DOCX 15 kb)Below is the link to the electronic supplementary material.


Objective: Attention deficit hyperactivity disorder (ADHD) is a common psychiatric disorder diagnosed in increasing proportions of children and adolescents. The psychostimulant methylphenidate has been considered the first-line pharmacological treatment for children and adolescents with ADHD for more than 60 years. Considering recent publications on methylphenidate for ADHD, we here give an overview of its effects in children and adolescents with ADHD, elicited by a well-disputed Cochrane review and narratively synthesise the evidence in the field. Method: We searched for systematic reviews and meta-analyses that investigated methylphenidate as an intervention for children and adolescence with ADHD compared with placebo or no treatment. We assessed the quality of the evidence using AMSTAR II. Results: We found 24 eligible systematic reviews and meta-analyses of which 11 were rated as high- quality evidence according to AMSTAR II. The evidence claiming that methylphenidate is beneficial in treating children and adolescents with ADHD was of very low certainty. The underreporting of adverse events in randomised clinical trials may impede an adequate depiction of the balance between benefits and harms. Conclusions: It appears that there is uncertain evidence on group-level to support the claim that methylphenidate is beneficial in treating children and adolescents with ADHD. Future randomised clinical trials and systematic reviews should include individual participant data, which would allow us to assess intervention effects across modifiers, like age, sex, ADHD subtypes, comorbidities, and dose. The attention deficit hyperactivity disorder (ADHD) diagnosis is based on persistent impairment of one or more of the following core symptoms: excessive inattention, hyperactivity, and impulsivity. Furthermore, symptoms must interfere with everyday life before the age of 7 years ICD-10) or 12 years DSM-5) 0 or 12 y,4. The d 0 or 12 The 2015 Cochrane review by Storebø and colleagues investigated the beneficial and harmful effects of methylphenidate as treatment for children and adolescents with ADHD ,7. StoreThere was a small beneficial effect of methylphenidate on quality of life . The evidence was rated as of very low-quality due to high risk of bias, indirectness, and selective outcome reporting .Methylphenidate significantly increased adverse events considered non-serious and the risks of serious adverse events could not be assessed due to lack of data . This reWe searched PubMed, the Cochrane Library, and BMJ Best Practice on 6 October 2020, and achieved 477 full text hits after removing duplicates and irrelevant publications. Two independent reviewers went through titles and abstracts of these and excluded 449 studies, leaving 24 included studies. A third reviewer resolved disagreements. In cases where any author of this article was also co-author in an included review, we excluded that co-author from the assessment process. We included 24 reviews or meta-analyses in English, published in 2013 and onwards that investigated methylphenidate as an intervention for children and adolescence with ADHD compared with placebo or no treatment. Reviews investigating multiple interventions were included if data on methylphenidate was reported separately and it was possible to differentiate from other interventions. Two reviewers using the AMSTAR II checklist assessed the 24 included studies ,29,30,31The updated 2018 guideline from the National Institute for Health and Care Excellence (NICE) recommends methylphenidate as the first-line pharmacological treatment for children over 5 and adolescents . There aTwo researchers from Mount Sinai Graduate Program in Public Health applied for inclusion of methylphenidate on the WHO Model List of Essential Medicines in December 2018 for children, adolescents, and adults with ADHD . The WHOUsing individual participant data from 39 patients in n-of 1-trials in their meta-analysis, Punja and colleagues. (2016) concluded methylphenidate to be effective for ADHD in children . The genUtilising methylphenidate as the pharmacological first choice of treatment for children and adolescents with ADHD was supported in a large systematic review and network meta-analysis by Cortese and colleagues (2018), who compared efficacy and tolerability of methylphenidate for ADHD to placebo alongside other medications . The autIn an efficacy and safety assessment of stimulants and non-stimulants on ADHD symptoms for children and adolescents, Cerrillo-Urbina and colleagues (2018) concluded that both treatments alleviate ADHD symptoms and that stimulants especially seemed to have a superior effect on inattention and hyperactivity. Their review included only four trials on methylphenidate which were all conducted before 2013 and therefore did not encompass any new evidence .Incorporating comorbidity in an effect analysis, a Cochrane review by Osland and colleagues (2018) investigated the effects of various pharmacological treatments, including methylphenidate for ADHD in children with comorbid tic disorder . They foWhen assessing the effects of methylphenidate, importance should be given to the balance between benefits as well as adverse effects.Adverse effects of methylphenidate commonly investigated and reported include inter alia insomnia, anxiety, growth suppression, reduced weight gain and gastrointestinal events like nausea, abdominal pain, and reduced appetite . Osland The 2018 Cochrane systematic review of non-randomised studies on methylphenidate and adverse events in children and adolescents with ADHD by Storebø and colleagues, showed that methylphenidate may be associated with a number of serious adverse events as well as a large number of non-serious adverse events in children and adolescents, which often lead to withdrawal of methylphenidate . The cerWhen comparing treatment with methylphenidate to non-pharmacologic interventions, Kemper and colleagues found that methylphenidate increased sleep disturbance and decreased appetite. All but two included studies, however, were rated as having insufficient certainty of evidence by the authors, for which reason they decided that no other outcomes could be investigated .Other serious adverse events of methylphenidate treatment for children and adolescents include the development of psychosis and cardiovascular problems. Investigating cardiovascular risks of methylphenidate and other pharmacological treatments for ADHD, Liu and colleagues could not exclude a modest elevated risk for sudden cardiac arrest and arrhythmia linked to the use of methylphenidate, based on confidence intervals. They advised that this risk be considered against the benefits of medication and suggested regular monitoring of heart rate and blood pressure .The underreporting of adverse events in randomised clinical trials may impede an adequate depiction of the balance between methylphenidate benefits and harms in children and adolescents with ADHD. The issue of underreporting adverse events is well known and has been investigated repeatedly ,55. In aNone of the included reviews of good quality from our search mentioned the effects of withdrawal symptoms. It is important to investigate collateral cognitive and emotional withdrawal effects such as s depression, poor concentration, agitation, irritability, and anxiety .Consequently, when comparing benefits and harms it seems there are substantial risks of harms, which may have been overlooked in previous publications . AgainstWe cannot of course ignore that some patients and clinicians experience advantages of methylphenidate. When looking at the evidence from clinical trials, the variance of the outcomes in the methylphenidate group does not seem to be larger than that of the placebo or no-intervention group. This makes it unclear whether there might be a differential effect between the groups . AdditioMany experienced clinicians and researchers find that methylphenidate gives symptom reduction in some children and adolescents with ADHD, albeit the proportion of this group is unclear. Although the average treatment effect may not be above the clinically significant level, beneficial effects in one or more subgroups can occur. One way to identify such subgroups is to conduct individual patient data (IPD) reviews. In this type of review it is possible to look for information on whether patient characteristics influence treatment outcomes . MoreoveIt appears that there may still be uncertain evidence on group-level to support the conclusion that methylphenidate would be beneficial in treating children and adolescents with ADHD. Future randomised clinical trials and systematic reviews should include individual participant data, which would allow us to assess intervention effects across modifiers, like age, sex, ADHD subtypes, comorbidities, and dose. These data must be present for both the short- and long-term effects of methylphenidate for children and adolescents. Only then, can we discover the subgroups of patients with ADHD that benefit the most from methylphenidate, as well as those that benefit the least.


It is unclear how pharmacological and non-pharmacological interventions compare with each other in terms of efficacy and tolerability for core symptoms and additional problems in adults with attention-deficit/hyperactivity disorder (ADHD). We aim to conduct the first network meta-analysis (NMA) comparing pharmacological and non-pharmacological interventions (or their combinations) in adults with ADHD.We will follow the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement for NMAs. We will search a broad set of electronic databases/registries and contact drug companies and experts in the field to retrieve published and unpublished randomised controlled trials (RCTs)  of medications (either licensed or unlicensed) and any non-pharmacological intervention in adults (≥18 years) with ADHD. Primary outcomes will be: (1) change in severity of ADHD core symptoms, and (2) acceptability . Secondary outcomes will include tolerability (drop-out due to side effects) and change in the severity of emotional dysregulation, executive dysfunctions and quality of life. The risk of bias in each individual RCT included in the NMA will be assessed using the Cochrane Risk of Bias tool-version 2. We will evaluate the transitivity assumption comparing the distribution of possible effect modifiers across treatment comparisons. We will perform Bayesian NMA for each outcome with random-effects model in OpenBUGS. Pooled estimates of NMA will be obtained using the Markov Chains Monte Carlo method. We will judge the credibility in the evidence derived from the NMA using the CINeMA tool (which includes assessment of publication bias). We will conduct a series of sensitivity analyses to assess the robustness of the findings.As this is the protocol for an aggregate-data level NMA, ethical approval will not be required. Results will be disseminated at national/international conferences and in peer-reviewed journals.CRD42021265576. The study will be conducted by a team with extensive expertise in the clinical assessment and treatment of attention-deficit/hyperactivity disorder (ADHD), as well as in advanced network meta-analysis (NMA) statistics.The protocol was designed and the study will be carried out with the involvement of patients and members of the public in the review team.We will include both published and unpublished data, systematically gathered by drug manufacturers and study authors.We will include, as outcomes, both ADHD core symptoms and related clinical problems, thus increasing the ecological validity of the study.The main limitation is that the proposed NMA will include aggregate-level data, rather than individual patient level data.Attention-deficit/hyperactivity disorder (ADHD) is the most common neurodevelopmental condition in children,7Both pharmacological and non-pharmacological  treatments are available for adults with ADHD.The current ADHD guidelines from the National Institute for Health and Care Excellence (NICE) recommend pharmacotherapy (stimulants followed by the selective norepinephrine reuptake inhibitor atomoxetine) as first-line treatment options for adult ADHD, with psychological therapies as second option.Therefore, there is a need for updated evidence synthesis regarding how non-pharmacological interventions—and different ways to deliver them —compare with each other, to pharmacologic treatments or to combinations of pharmacological and non-pharmacological interventions in terms of efficacy and tolerability on specific relevant outcomes  in adults with ADHD.A well-powered RCT would be suited to compare pharmacological and non-pharmacological options, but there are obvious financial and logistic constraints in conducting well-powered RCTs comparing all interventions for ADHD in adults. Network meta-analysis (NMA), which allows for the comparison of two or more interventions even when they have not been compared head-to-head in the studies included in the meta-analysis,A scoping search in PubMed/Medline , PsycInfo and Embase (up to 1 October 2021) using search terms for ‘ADHD’, ‘adults’ and ‘network meta-analysis’ did not find any NMA including, in the same network, pharmacologic and non-pharmacologic interventions for adults with ADHD. Based on our searches, no protocol for such NMA has been registered in PROSPERO or other registries at the time of writing.Therefore, we aim to conduct the first systematic review/NMA of published and unpublished RCTs to assess the comparative efficacy and tolerability of UK licensed and unlicensed medications for ADHD, non-pharmacological treatments, or their combination, on ADHD core symptoms severity and related dysfunctions  in adults with ADHD.The methods of the proposed study are based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement and its extension for NMA.The protocol of the present NMA is preregistered in PROSPERO.19We plan to start the study on 1 March 2022 and to complete it by 1 March 2024.ClinicalTrials.gov, with no language/type of document restrictions. For the specific syntax for each database, see We will update the search for RCTs of medications for ADHD from an NMA10.1136/bmjopen-2021-058102.supp1Supplementary dataWe will also search the US Food and Drug Administration, European Medicines Agency and relevant drug manufacturers’ websites for RCTs of medications. We will also endeavour to gather relevant unpublished data for pharmacological and non-pharmacological interventions by contacting drug companies, study authors and the members of key scientific organisations of ADHD worldwide. Specifically, we will contact the European Network of Hyperkinetic disorder (Eunethydis), the World ADHD Federation, the he American Professional Society of ADHD and Related Disorders (APSARD) and the Canadian ADHD Resource Alliance (CADDRA) to advertise the study and query about the existence of any eligible unpublished study.et al)20We will include parallel or cross-over RCTs of at least 1-week duration for pharmacological treatment, in line with prior work,We will retain RCTs including adults (≥18 years) with a formal diagnosis of ADHD according to DSM-III, DSM III-R, DSM-IV (TR), DSM-5, ICD-9, ICD-10 or ICD-11. We will not restrict our search by ADHD subtype or presentation, sex, ethnicity, IQ, socioeconomic status or comorbidities.or lisdexamphetamine (or other amphetamines) as first-line pharmacological treatment for adults. Any type of non-pharmacological intervention will be considered.As in prior work,The pharmacological control condition will be a pill placebo; non-pharmacological controls will include waiting list, treatment as usual, clinical management, active control in psychotherapy, and psychological placebo (sham).et al;et al,et al.23Primary outcomes: (1) change in severity of ADHD core symptoms, according to a standardised rating scale.We will select studies, and extract/collect data in a two-step process. First, two independent investigators will screen the titles and abstracts we identified. Second, two independent investigators will obtain and read the full texts of all potentially relevant studies and determine the final list of studies to include. Any disagreement will be resolved by senior investigators. We will extract data into prespecified data extraction forms.The risk of bias in each individual RCT included in our NMA will be assessed using the Cochrane Risk of Bias tool-version 2 (RoB-2), as recommended in The Cochrane Handbook of Systematic Reviews of Interventions.Bias arising from the randomisation process.Bias due to deviations from intended interventions.Bias due to missing outcome data.Bias in measurement of the outcome.Bias in selection of the reported result.We will use the appropriate templates for randomised parallel-group and cross-over trials, respectively.For continuous outcomes, we will use mean difference (MD) as a measurement of treatment effect, with the relative 95% CI, when studies assessed the outcome with the same instruments; standardised mean difference  when studies used different instruments.28For dichotomous outcomes, we will calculate the OR and relative 95% CI. Missing dichotomous outcome data will be handled according to the intention-to-treat principle. Participants who drop out after randomisation will be considered as having a negative outcome.In each pairwise comparison, patient characteristics, treatments and outcome deﬁnitions of included studies should be similar.It is appropriate to use NMA if the assumption of transitivity can be defended. Transitivity holds when the distributions of the potential effect modifiers, like study and patient-level covariates, are balanced across all pairwise comparisons.First, we will conduct conventional pairwise meta-analyses with a random-effects model in STATA V.16.1 for all outcomes and comparisons with at least two studies. Then, we will perform Bayesian NMA for each outcome with random-effects model in OpenBUGS,33We will estimate heterogeneity variances for each pairwise comparison in standard pairwise meta-analyses and assess the presence of statistical heterogeneity by visually inspecting the forest plots and calculating the I-squared statistic.Statistical disagreement between direct and indirect effect sizes (incoherence) will be evaluated globally, by comparison of the fit and parsimony of consistency and inconsistency models, and locally, by calculation of the difference between direct and indirect estimates in all closed loops in the network.We will then use the Surface Under the Cumulative RAnking (SUCRA) curve to measure, for any outcome, the probability each treatment is the best option among all treatments included in the network treatment and express the SUCRA measure as a percentage.33 40http://cinema.ispm.ch/).43We will assess the certainty of evidence derived using CINeMA , one of the largest UK charities of patients with ADHD, has played a central role in the development of this protocol since its initial design. During the preparation of the present proposal, Ms. Bilbow: liaised with representatives (patients) of ADDISS, and ADHD Europe to gather their feedback on the proposal; based on the feedback form patients, critically commented on the overarching plan of the application, highlighting that it covers an important gap perceived as crucial by patients with ADHD and their families; noted the importance of comparing different types of non-pharmacological interventions given the patchy provision across the UK and uncertainties around the evidence base supporting at least some types of non-pharmacological approaches; recommended inclusion of quality of life as a secondary outcome measure.As this is a protocol, no patients were directly involved in this study.As this is the protocol of an aggregate-data level NMA, no ethical approval will be needed.On publication, the full data set of the NMA and the codes for the analyses will be available online freely in Mendeley Data, a secure online repository for research data. The results of the study will be disseminated nationally, via conferences organised by groups of people with lived experience  and professional organisations . Results will also be disseminated internationally via conferences  and publications in peer-reviewed journals in the field of psychiatry/psychology and general medicine.


Dear Editor,Translational Psychiatry, Takahashi et al.1 reported their analysis of shared polygenic risk scores suggest a shared genetic background for both attention deficit hyperactivity disorder (ADHD) and narcolepsy. By another method, we described a similar association between ADHD and narcolepsy. In a paper delivered at the 1995 American Academy of Neurology2, we reported three families each in two generations with concurrent ADHD, hypersomnia defined by pupillometry3 without sleep log evidence of sleep disorder and both HLA markers DR-2/DQw-1 employed at that time associated with narcolepsy (Fig. In a recent issue of 4. Clinically, we have observed late adolescent ADHD patients who will not drive automobiles without their alerting medications for fear of falling asleep. We have additionally observed an increased frequency of these HLA markers as well as hypersomnia in individuals with dyslexia, both with and without ADHD5. However, either condition may occur independent of these HLA markers.Our subsequent studies have suggested a frequency of HLA markers associated with narcolepsy more than double than anticipated in Caucasians in individuals with behavioral and cognitive evidence of ADHD6.The social significance of such an association if valid is that an unknown percentage of ADHD children/adolescents/adults may require alerting medication to become safe adult drivers, as sleepiness increases the risk of motor vehicle accident by a factor of 2.5


BackgroundGlobally, attention deficit hyperactivity disorder (ADHD) is the most common neurobehavioral disorder that affects children. In 2011, there was an ADHD diagnosis prevalence of around 8% among children (4-17 years) in the US. ADHD-affected children are more prone to physical injuries such as physical trauma, accidental poisoning, burns, etc. This study was aimed to evaluate the association of ADHD with severe injuries, the influence of age and gender on this association, and the impact of ADHD medications on the frequency of such injuries.MethodologyThis study was conducted in three governmental and three private settings in Aseer region. The files of children who were diagnosed with ADHD in the study settings were reviewed for a 12-month time period. Data were extracted from the medical files using a pre-structured data extraction sheet to avoid errors and inter-rater bias. The extracted data included child gender, age, duration of disease, and injury-related data. A brief questionnaire had been applied to mothers regarding mothers' attitudes towards injuries among their children, adherence to medications, as well as the reasons for non-adherence to medications and clinical visits in a non-adherent group during the clinic visit.ResultsOne hundred and sixty-three children with a diagnosis of ADHD completed the study. The affected children were aged between two and 15 years (mean: 7.8 ± 2.9 years). An exact of 116 (71.2%) children were males. An exact of 70 (42.9%) affected children had trauma. The most-reported traumas were superficial injuries (84.3%), burns (48.6%), fractures (37.1%), deep injuries (31.4%), and broken or lost teeth (28.6%). About 52% of the children were adherent to medications and their clinical visits. Among the non-adherent group, the most reported reasons were parents’ care and attention (20.5%), followed by the COVID-19 pandemic and delay in visits times (16.7%). Regarding mothers' attitudes towards injuries among children with ADHD, 49.1% of the mothers agreed that there is an association between a child with ADHD and being traumatized while 22.7% said there was no relation.ConclusionsIn our cohort, the majority of the children with ADHD were boys at primary school age. Association of the history of the disease with trauma was not uncommon, and most injuries were not severe, but burns and deep injuries were reported among considered portions. Attention deficit hyperactivity disorder (ADHD) is a well-known neurobehavioral disorder with childhood-onset and becomes apparent in the preschool and early school years. It is characterized by persistent lack of attention, overactivity, and impulsivity . The thrPrevious studies have reported a 4%-12% ADHD incidence among children aged six to 12 years -7. OtherPrevious studies have demonstrated ADHD-affected children are more prone to physical injuries such as physical trauma, accidental poisoning, burns, etc. This study was aimed to evaluate the association of ADHD with severe injuries, the influence of age and gender on this association, and the impact of ADHD medications on the frequency of such injuries.A descriptive cross-sectional study was conducted in Abha Maternity and Children’s Hospital, Khamis Mushait Maternity and Children’s Hospital, Abha Psychiatric Hospital, Hayat National Hospital, Abha Private Hospital, Saudi German Hospital (Aseer), and Daweni Medical Center. Files for children who were diagnosed with ADHD in the study settings were reviewed for a 12-month time period. Data were extracted from the medical files using a pre-structured data extraction sheet to avoid errors and inter-rater bias. Data extracted included child gender, age, and disease duration. Injury history since diagnosis, including the type of injury, frequency of injuries, and required medical care, were also reviewed. A brief questionnaire was applied to mothers regarding mothers' attitudes towards injuries among their children, adherence to medications, as well as the reasons for non-adherence to medications and clinical visits in a non-adherent group during a clinic visit.Data analysisThe data were statistically analyzed using SPSS version 22 . Two-tailed tests were used for statistical comparisons. Statistical significance was defined by a p-value of < 0.05. We performed descriptive analysis for all variables, including child demographic data, trauma types and frequency, childrens' adherence to treatment, and mothers’ attitude towards disease relation with trauma. The trauma history of children was assessed on the basis of their personal data and adherence to treatment. In addition, the Pearson chi-square test was used to assess the correlations.A total of 163 children with a diagnosis of ADHD completed the study. The ages of the affected children ranged from two to 15 years (mean: 7.8 ± 2.9 years). An exact of 116 (71.2%) children were males , with prevalence rates of pedestrian- and bicyclist-related injuries of 27.5% and 13.8%, respectively . They alAppropriate treatment and psychological therapy may be effective in reducing the injury- and mortality-related risk among ADHD-affected children, making it possible to reduce the risk of injury and death among children with ADHD. So, the use of adequate ADHD screening techniques is recommended for children with frequent injuries.Our results demonstrated that the majority of the children with ADHD were boys at primary school age. History of disease-associated trauma was not uncommon, and most injuries were not severe, but burns and deep injuries were reported among considered portions. Also, the need for medical care due to childhood trauma was considerably reported, which means more care should be paid, and mothers need health education sessions to enhance their awareness regarding how to deal with a child with ADHD and the specific environmental constraints in their home to avoid injuries. Future studies must focus on assessing the impact of early screening for children with ADHD-related behaviors. Such techniques could facilitate early diagnosis, which could, in turn, avoid the development of severe ADHD-related impairments from childhood to adulthood.


Patients were followed for up to 12 months after GXR initiation and, if they had received prior ADHD pharmacotherapy, for 12 months before GXR initiation. The primary outcome was change in ADHD symptoms and functionality based on physician assessments, classified as improvement, no change, or worsening relative to the time of GXR initiation. Treatment-emergent adverse events (TEAEs) were evaluated. Clinical outcomes were also analyzed post hoc according to whether GXR treatment was received as monotherapy or adjunctive therapy, and by select psychiatric comorbidities. Exploratory analyses were conducted in patients who had received prior ADHD pharmacotherapy to evaluate clinical outcomes after initiating GXR.Improvements in ADHD symptoms were reported for 232/330 (70.3%) patients. Functional improvements in school performance and home life were reported for 213/330 (64.5%) and 209/330 (63.3%) patients, respectively. The most frequent TEAEs (≥ 5%) were somnolence, headache, insomnia, presyncope, and decreased appetite. Improvements in ADHD symptoms were observed when GXR was received as either monotherapy (35/60 [58.3%]) or adjunctive therapy (197/270 [73.0%]). Improvements in ADHD symptoms and functionality were observed in the majority of patients with select psychiatric comorbidities. Among patients who had experienced worsening of symptoms with prior ADHD pharmacotherapy, 44/54 (81.5%) experienced symptom improvement, 33/44 (75.0%) who had previously experienced worsening of school performance improved, and 34/48 (70.8%) who had previously experienced worsening of home life improved.In Canadian routine clinical practice, most children and adolescents with ADHD treated with GXR experienced improvements in ADHD symptoms and in functionality both at school and at home.The online version contains supplementary material available at 10.1186/s13034-021-00402-5. Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder with childhood onset characterized by a pervasive pattern of age-inappropriate and excessive inattention and hyperactivity/impulsivity . The estThe socioeconomic burden of ADHD is considerable, impairing many aspects of children’s lives and their families, and negatively affecting academic performance and interpersonal relationships. Specific manifestations may include inattention and distractibility in daily routines, impulsive behavior, or missing social cues . In younIn the United States, healthcare costs for children and adolescents with ADHD have been estimated at $US 7.9 billion annually (2005 costs) . In Cana2-adrenoceptor agonist, GXR can also be used as adjunctive therapy to stimulants [Both psychosocial and pharmacologic interventions are used for ADHD treatment. Combination therapy with approved medication and behavioral therapy is the preferred model for children aged ≥ 6 years and adolescents . Stimulaimulants , 15.2-adrenoceptor agonist GXR in routine Canadian clinical practice.Real-world evidence provides valuable knowledge beyond the ideal conditions of a clinical trial, and several such studies have assessed usage patterns and costs of non-stimulants in patients with ADHD , 17. HowThis study was a retrospective medical chart review in children and adolescents with ADHD recruited from 10 sites by Canadian community- or hospital-based pediatricians, child psychiatrists, or family doctors specializing in ADHD. Included children (6–12 years) and adolescents (13–17 years) had diagnosed ADHD, had initiated treatment with GXR (monotherapy or adjunctive therapy), and had ≥ 6 months of medical chart data post-initiation of GXR . Patients could have been treatment naive or received other pharmacotherapy before GXR initiation. In treatment-naive patients, the observation period of the chart review began at treatment initiation, whereas in patients who had received prior ADHD pharmacotherapy, the observation period started 12 months prior to GXR initiation. The chart review observation period ended at ≤ 12 months after GXR initiation. If GXR was discontinued, the reason for discontinuation was noted but no other follow-up data were extracted after the discontinuation visit.Data were transcribed from patient charts to case report forms (CRFs) by the site investigator or designated staff and sent to a central database. No patient identifying information was recorded; patients were given encrypted random study identification numbers. Data on patient demographics and clinical characteristics were extracted from patient charts per standard of care for ADHD. At ADHD diagnosis, these data included diagnosis date, sociodemographics , medical history, and comorbidities. At GXR initiation, data extracted included reason for GXR initiation, prior non-pharmacologic treatments for ADHD or comorbid conditions, and prior pharmacologic treatments, including stimulants, non-stimulants, and atypical antipsychotics (AAPs) for ADHD or comorbid psychiatric conditions/symptoms. At GXR initiation and for its duration, covariates included GXR information  and pharmacologic treatment for ADHD or comorbid psychiatric symptoms. If GXR was discontinued, reasons for discontinuation and any subsequent ADHD-related pharmacologic treatment regimen were recorded, and no additional follow-up details were extracted following the discontinuation visit.Extracted outcome data were from the time prior to (for patients receiving prior pharmacologic treatment only), at GXR initiation, and for its duration (≤ 12 months). ADHD symptoms and functionality were measured using the General Physician Symptom Assessment and General Physician Functional Assessment (school grades/performance and homelife), respectively. Rating scale data on ADHD symptoms and functionality, if available in patient charts, were also extracted and evaluated. Symptom ratings scales included Swanson, Nolan, and Pelham-IV (SNAP-IV-26) , NationaTreatment-emergent adverse events (TEAEs) occurring during GXR treatment were coded using the Medical Dictionary for Regulatory Activities (MedDRA) version 20 and described by the proportion of patients experiencing a TEAE within each Preferred Term and System Organ Class.Charts from a minimum of 252 and maximum of 444 patients were required. In research by Cutler et al. , symptomIn Cutler et al. , 77.3% oSummary statistics were calculated for all study variables, including mean, median, standard deviation (SD), 95% CI of the mean, and frequency distributions for continuous scale variables.The primary analysis was change in ADHD symptoms and functionality, assessed by the proportion of patients showing improvement versus no change versus worsening. For patients without previous ADHD treatment, this categorization was based on assessment of the patient compared with the previous visit (beginning with the comparison of the first assessment post-GXR initiation to status at initiation). For patients who had received prior ADHD pharmacologic treatment, the pre-GXR value corresponded to the overall response  to the last treatment regimen administered prior to GXR initiation. An improvement/worsening of symptoms or function was defined as a categorization of patient response as improved or worse, respectively, for two consecutive visits. The best symptom and functionality responses were described, corresponding to the best respective responses registered during the post-GXR initiation observation period while receiving GXR.Post-hoc analyses (unspecified in the protocol) included assessments of symptoms and functionality whether GXR treatment was monotherapy/adjunctive therapy, if patients had been initiated on GXR to reduce use of AAPs, and according to psychiatric comorbidities of interest .Data from patients who had received ADHD pharmacologic treatment before GXR and had ≤ 12 months of data following GXR initiation, a subset not considered in power calculations, were examined in exploratory analyses. The objective was to assess the impact on clinical outcomes of switching to GXR or adding GXR to current ADHD treatment. The pre-GXR value (prior period) corresponded to the overall response  to the last treatment regimen administered before GXR initiation. The analyses detailed for the primary objective were repeated in this subgroup, although the post-hoc breakdown of results  was not conducted. The comparison of the response rate (improvement vs no change vs worsening) of General Physician Symptom and Functional Assessments before and after GXR initiation was conducted with the extension of McNemar’s test (Bowker’s test); two-tailed test. The null hypothesis was that the percentages are equal before and after GXR initiation, i.e., during the baseline period and post-GXR initiation observation period .As this was a retrospective chart review, no missing data could be retrieved. However, cross-validation was performed, and erroneous data were clarified with physicians. Partial dates were completed using the most conservative approach when required to determine duration of observation, treatment exposure, and incidence of adverse events. Otherwise, all analyses were conducted on available data with no data imputation.Study sites were activated on a rolling basis beginning on 5 October 2016; database lock occurred on 16 June 2017.In total, 330 charts were screened, and all patients were included in the analysis  patients. The most frequently reported conditions experienced by ≥ 5% of patients were oppositional defiant disorder , learning disability , anxiety , autism spectrum disorder , and tic .A total of 270 (81.8%) patients concomitantly used other pharmacological treatments for ADHD and comorbid psychiatric conditions while on GXR. The most frequently used medications included methylphenidate , lisdexamfetamine , melatonin , centrally acting sympathomimetics , apriprazole , and risperidone . Six (1.8%) patients used clonidine, 1 (0.3%) patient used trazodone, and 40 patients used SSRIs .The most common reasons for GXR initiation were non-optimal control of ADHD symptoms, to improve response to stimulants, to extend duration of effect of stimulants, and to avoid increasing doses of ADHD stimulants  patients (Table Improvements in ADHD symptoms were observed in 35/60 (58.3%) patients receiving monotherapy and 197/270 (73.0%) patients receiving GXR adjunctive therapy. Similar improvements were seen in functionality assessments of school performance  and homelife .Of the 44 patients initiated on GXR to reduce use of AAPs, ADHD symptom improvements were experienced by > 70%, including > 55% of patients in school performance and homelife functionality Fig. . AAPs usPatients with comorbid autism spectrum disorder, oppositional defiant disorder, anxiety, or learning disability experienced improvements in ADHD symptoms and functionality consistent with the primary findings Table .Table 2BIn the subgroup who had received prior pharmacotherapy, a greater proportion of patients who had reported worsening ADHD symptoms on prior pharmacotherapy experienced improvements on GXR compared with those reporting no changes Table . SimilarThis retrospective chart review deepens our understanding of GXR use beyond the clinical trial setting, suggesting that children and adolescents with ADHD receiving GXR in real-world clinical practice experienced improvements in ADHD symptoms and functionality. These improvements were evident for the overall population  and patients who had experienced worsening symptoms or functionality with ADHD pharmacotherapy immediately before GXR initiation . Our data suggest that, in Canada, GXR is less commonly used as monotherapy than as adjunctive treatment. Post-hoc analyses demonstrated improvements in ADHD symptoms in 58.3% of patients using GXR as monotherapy and 73.0% of patients using GXR as adjunctive therapy, corroborating randomized, double-blind, placebo-controlled, clinical trial data demonstrating that GXR is clinically efficacious as either monotherapy or adjunctive therapy –25.2-adrenoceptor agonist. The majority of α2-adrenoceptors are expressed at postsynaptic neurons of the prefrontal cortex, and have been shown to regulate cognitive functions [GXR is a selective αunctions . Althougunctions , 34. Thiunctions , 23. Stiunctions , 12. Stiunctions .In this study, a relatively high proportion of patients continued treatment beyond 12 months . For comparison, albeit from different populations and methodologies, three large database analyses from Taiwan, Canada, and the United Kingdom found persistence with stimulant and non-stimulant ADHD medications at 1 year ranged from 41.2 to 77.0% –37. We a®) [The observed safety profile in our study is generally consistent with that described in the GXR product monograph (Intuniv XR®) , includi®) , or thatMany physicians in Canada use AAPs in complicated or comorbid cases of ADHD ; howeverThis was a real-world study of medical chart review data from patients with ADHD, and so included patients from a naturalistic setting. This means that, unlike in the clinical trial setting where strict exclusion/inclusion criteria are applied, patients who would be typically seen in clinical practice were included, such as those with confounding comorbidities. Here, many patients were reported to have ≥ 1 comorbid psychiatric condition, including oppositional defiant disorder (27.9%), learning disability 21.2%), anxiety (16.1%), and autism spectrum disorder (10.6%). The results of our post-hoc analysis suggest that GXR is effective in improving ADHD symptoms and functionality in patients with ADHD with different psychiatric comorbidities or without comorbid psychiatric conditions. These findings are consistent with another study showing GXR to be effective in reducing ADHD symptoms in patients with ADHD and comorbid oppositional symptoms [.2%, anxiThe limitations of the study reported here include the inherent limitations of retrospective medical record analysis; the patients selected for study inclusion represented a convenience sample. The vast majority of patients were from Ontario and 82% of participants were Caucasian. Findings may therefore not be generalizable to or fully representative of the broader ADHD population in Canada. The analysis of symptom improvement during previous therapy was exploratory and limited to improvement, no change, or worsening from the overall response to the last treatment regimen. In addition, as this was a real-world study, outcomes may have been affected by factors such as adherence, access, long-term duration of therapy, and the presence of comorbidities and concomitant medications. However, compared with patients included in clinical trials, this population may represent a more accurate view of typical patients seen in routine practice.Although data from different sites were standardized by transcription onto CRFs, it should be acknowledged that there may be inherent differences in data collection methods. Specifically, some sites used standardized methodology such as rating scales that could be used to support and analyze data further, but these data were not available for all patients or sites. Also, although the data were interpreted as accurately as possible using available clinical notes, some assumptions were made. Therefore, study findings should be interpreted in consideration of these limitations.The maximum dose of GXR is 7 mg daily for adolescents when used as monotherapy. However, in our study, the highest dose reported was only 5 mg. This observation may relate to the fact that GXR was predominantly used as adjunctive therapy (for which the maximum recommended dose is 4 mg), or perhaps the clinicians treating these patients adopted a conservative approach to GXR dosing.In routine clinical practice in Canada, most children and adolescents with ADHD treated with GXR experienced improvements in ADHD symptoms, and in functionality at both school and home. Safety data in this chart review are consistent with those reported in clinical trials. Additionally, this real-world evidence corroborates the efficacy of GXR observed in randomized controlled trials and demonstrates the effectiveness of GXR as adjunctive therapy and, albeit with a smaller sample size, as monotherapy.Additional file 1: Table S1. Patient disposition and sociodemographics. Table S2. Characteristics of GXR treatment from initiation through end of study.