Somatic disorders occur more often in adult psychiatric patients than in the general adult population. However, in child and adolescent psychiatry this association is unclear, mainly due to a lack of integration of existing data. To address this issue, we here present a systematic review on medical comorbidity in the two major developmental disorders autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD) and formulate clinical recommendations. The literature was searched using the PubMed and PsycINFO databases (2000–1 May 2016) with the keywords “[((child and adolescent) AND (Autism OR Attention Deficit Hyperactivity Disorder* OR ADHD)) AND ]. Two raters independently assessed the quality of the eligible studies. The initial search identified 5278 articles. Based on inclusion and exclusion criteria 104 papers were selected and subsequently subjected to a quality control. This quality was assessed according to a standardized and validated set of criteria and yielded 29 studies for inclusion. This thorough literature search provides an overview of relevant articles on medical comorbidity in ADHD and/or ASD, and shows that medical disorders in these children and adolescents appear to be widespread. Those who work with children with ASD and/or ADHD should be well aware of this and actively promote routine medical assessment. Additionally, case–control studies and population-based studies are needed to provide reliable prevalence estimates. Future studies should furthermore focus on a broader evaluation of medical disorders in children and adolescents with ADHD and/or ASD to improve treatment algorithm in this vulnerable group. Medical disorders occur more often in adult psychiatric patients than in the general population . MoreoveThe increased risk for mental health problems has also been found in children with medical disorders. Findings of the Isle of Wight studies of Sir Michael Rutter and colleagues  startingSeveral systematic reviews have been published on the association between specific medical disorders and child psychiatric disorders, for instance on the association between epilepsy and psychopathology , atopic Following the data from reviews and clinical studies, Merikangas and colleagues performed a study on comorbidity of mental and physical conditions and functional impairments in 9014 children and adolescents . In partIn a previous pilot study we evaluated the outcome of medical screening at referral in children and adolescents with different psychiatric disorders. This screening revealed new somatic findings in 56% of the subjects . These fThese findings all contribute to the increasing awareness about the association between somatic and mental symptoms in developmental disorders and may suggest potential mechanisms such as common genetic pathways . Also, tMost of the available literature on medical disorders in child and adolescent psychiatric disorders relates to ASD and ADHD, but there is a lack of integration of existing data, hampering the interpretation of findings. Therefore, this systematic review focuses on the association of medical disorders with autism and/or ADHD in children and adolescents and provides recommendations for future studies. Our hypothesis is that children with ADHD and ASD are at increased risk for a broad spectrum of medical disorders.The literature was searched using the PubMed and PsycINFO databases (January 2016) with the following keywords: [((child and adolescent) AND (Autism OR Attention Deficit Hyperactivity Disorder* OR ADHD)) AND ]. To be included in the present review, the articles had to be written in English language and published between 2000 and the first of May 2016.First, the papers were screened on title and abstracts, which was conducted independently by two of the authors (JM and FV) in order to assess the eligibility of the studies. Second, this selection of papers was screened based on the full text. The third author (WS) was consulted in case of differences in scoring by the other two authors. The inclusion and exclusion criteria were as follows.Sample subjects had to fulfill criteria for autism spectrum disorders (ASD) or attention deficit hyperactivity disorders (ADHD) by DSM-IV , DSM-IV-A medical or somatic disorder diagnosed by a clinician, from National Health Surveys or databases, or parents’ report.The age of the study participants was 18 years or younger including population-based studies started during childhood with follow-up >18 years.Inclusion criteria:Study design: case report, case series, letter to the editor, editorial, or data solely presented by means of a poster presentation.Study focus: intervention studies in which subjects were selected for pharmacological treatment of ADHD, exposure on chemicals, effects of dietary supplementation, perinatal complications and studies including mental retardation and/or syndromes.Exclusion criteria:Comparison group(s): the presence of at least 1 comparison group (control group), preferably a sample of healthy children from the same population or region as the children with medical disorders or ASD/ADHD.Sample selection: a random selection strategy should be used.Design: a case–control design based on quantitative information or population-based cohort studies.Diagnostic validity: DSM criteria, ICD 10 by clinicians .Outcome measures: medical disorder or ASD/ADHD.Statistical analyses: hypothesis testing using appropriate statistical analyses should be performed.Third, the quality of each study was assessed according to a standardized and validated set of criteria based on the protocols of the Cochrane Database of Systematic Reviews . The papThe initial search yielded in total 5278 papers . 4665 papers were excluded according to the title and/or the abstract and 451 were excluded based on the full text. The remaining 104 papers were scored of which 29 papers were considered of high quality (5 or 6 points) and presented in this review. Two of these 29 papers focused on both ADHD and ASD, and are therefore listed in both tables  3.40) in later life . GreaterGentile et al. found similar rates of contact with Herpes Simplex Virus 1 and Herpes Simplex Virus 2 between children with ASD and healthy controls .The study of Puig-Alcatraz et al. found that the increase in homocysteine concentration, suggestive for disorders of the immune system, was significantly correlated with the severity of the deficit in communication skills in children with ASD, but was unrelated to deficit in socialization or repetitive/restricted behavior compared to typically developing children .Contrary to the study of Jynouchi et al., Zerbo et al. reported that allergies and autoimmune diseases were diagnosed significantly more often among children with autism than among controls  = 1.22, 95% confidence interval (CI) 1.13–1.31; autoimmune disease: 1 vs. 0.76%, OR = 1.36, 95% CI 1.01–1.83), and asthma was diagnosed significantly less often  . FurtherThe study of Valicenti et al. found that children with ASD had a significantly higher rate of gastro-intestinal (GI) symptoms than children with either typical development or other developmental disabilities  . There wp value < 0.0001).The longitudinal population-based study of Mouridsen et al. found no evidence that patients with infantile autism (IA) were more likely than controls to have defined gastro-intestinal diseases during a 30.3-year observation period (30.5% against 30.7%) . Only dip < 0.001) [In the study of Wang et al., parents retrospectively reported significantly more GI problems in children with ASD  compared with their unaffected siblings  (< 0.001) . The 2 mThe increased prevalence of GI symptoms was also found by Chandler et al. In this study, 46.5% of children with ASD had at least one individual lifetime GI symptom compared with 21.8% of typically developing children and 29.2% of the children with special educational needs . No assop = 0.22; odds ratio = 1.5; 95% confidence interval = 0.8–2.6). Interestingly, only hernia was significantly associated with autism 11.2 vs 4.7% . There were no children with inflammatory GI diseases, such as Crohn’s disease or ulcerative colitis in the autism group. Hence, in this study people with autism had about the same frequency of gastric, intestinal and hepatic diseases as had controls [The study of Mouridsen et al. compared prevalence rates of gastro-intestinal tract diseases  in patients with PDD-NOS. In this study, conducted with data from the Danish National Hospital Register, the difference in prevalence of children with autism (24.7% (22/88)) and at least one diagnosis of any disease of the gastro-intestinal tract was not statistically significant (control group 18.2% (47/258))  and daytime urinary incontinence (25.0 vs 4.7%) in children with ASD compared to controls. Furthermore, ASD children had more lower urinary tract symptoms (LUTS) especially urgency and postponement, and they needed a longer time to become dry and continent .Mouridsen et al. studied the prevalence of epilepsy among patients with Asperger’s syndrome using the Danish National Hospital Register . In a fop-value < 0.01) compared to controls. Also, they were more likely referred to the physiotherapist/ergotherapist , speech therapist  and ear–nose–throat specialist  [Van Tongerloo et al. investigated the presence of characteristic complaints of children with ASD presenting to the general practitioners’ practice, in order to enhance early detection and reduce the delay in diagnosing ASD. This study found that children with ASD presented with more traumata (luxations and distortions)  .n = 9626) [n = 4936) and the control group .Using data from the Swedish Patient Register, Butwicka et al. studied the prevalence of ASD in men with hypospadias ( = 9626) . HypospaIn Table This review includes 12 papers on the association between ADHD and immunological disorders. The study of Leslie et al.  showed tp-value = 0.007) [The study of Sanchez et al. indicated that frequency of anti-basal ganglia antibodies (ABGA) in children with ADHD (non-comorbid with obsessive–compulsive disorder or tics) does not differ from that in matched controls (4 vs 4%), despite the fact that our ADHD patients had had more recent pharyngeal group A beta-hemolytic streptococcus GABHS infections than the controls  .With regard to atopy, the study of Schmitt et al. found a prevalence of ADHD among patients with atopic eczema (AE) of 5.2 and 3.4% among controls. Allergic comorbidities  were not significantly associated with ADHD .p-value = 0.0048) and allergic rhinitis in children with ADHD  [p-value > 0.05).The study of Suwan et al. showed significantly increased rates of allergic sensitization (= 0.008) . On the p-value < 0.001) [In a population-based study of Tsai et al. allergic rhinitis patients were more likely to have ADHD than the general population (< 0.001) .p-value < 0.001) [The association between allergy and ADHD was also found by Shyu et al. In their study, allergic children have a higher risk for developing ADHD in comparison with the general population (< 0.001) . AllergiChen HJ et al. found a significant association between previously diagnosed diabetes mellitus type 2 and ADHD in children aged 5–15 years  . There wp-value < 0.001, asthma  [Using the National Health Insurance Research Database, Chen MH et al. showed that patients with dual diagnoses of ADHD and tic disorder had a significantly higher prevalence of allergic diseases including allergic rhinitis, asthma, atopic dermatitis, allergic conjunctivitis than the ADHD alone group, the tic alone group, and the control group  .The study of Tsai et al. found a higher rate of allergic disease in children with ADHD compared to controls, particularly allergic rhinitis (OR 1.80 95% CI 1.69–1.93), and allergic conjunctivitis  [The study of Bekdas et al. presented that patients with ADHD displayed significantly higher positivity for measles IgG  . When paChen MH et al. found that the presence of any atopic disease in early childhood increased the risk of developing ADHD (HR: 1.97) in later life . Greaterp-value < 0.001) [Using data from the Neurodevelopmental Genomics Cohort Study, Merikangas et al. showed that children with central nervous system conditions (seizures and epilepsy) were significantly more likely to have ADHD  . There wp-value = 0.03) [The study of DeMaso et al. found that adolescents with d-transposition of the great arteries showed increased rates of attention deficit/hyperactivity disorder compared to healthy controls  . In the  = 0.03) . Among tThe population-based study of Silva et al. showed that children under 4 years with ADHD were 70% more likely to be admitted to a hospital compared with controls . AdmissiNext to ASD, Butwicka et al. also studied the prevalence of ADHD in men with hypospadias, and found an increased risk of ADHD in men with hypospadias  .The main finding of this systematic review is that medical disorders in children with ASD and ADHD appear to be widespread, e.g., can manifest across different medical areas, such as immunology, neurology and gastroenterology. Although it was not possible to extract prevalence data for the medical disorders, a reasonable number of studies could be included in this review, which supports the notion that children and adolescents with developmental disorders such as ADHD and ASD often suffer from medical disorders that needs to be investigated and addressed . LikewisIncreased awareness about the prevalence and types of comorbidity of medical disorders in developmental disorders is important for several reasons. It is first of all relevant for treatment and care for patients and their parents. Also, it may provide important information for fundamental research and could help to create a better understanding of the disease etiology of ASD and ADHD. Furthermore, insight in specific patterns of comorbidity may have important implications for the development of effective interventions for these disorders .However, most of the studies that were identified by our initial search did not reach the required level of quality to come to more profound interpretations, because they were hampered by limitations in study design, in limited case–control matching and/or relied on parent, teacher or self-report of symptoms rather than systematic diagnostic assessments by experts.First, most studies provide cross-sectional data thus limiting assessment of temporality and inference of causal pathways for the various conditions studied. Second, most studies examine the impact of a single medical comorbid condition, and studies that looked at a broad range of comorbid medical conditions are scarce. Third, the included studies sometimes show inconsistent results.There are also limitations related to the design of this systematic review. First of all, given the amount of research in child psychiatry, it has been decided to limit the current systematic review to the two main developmental disorders: ASD and ADHD. Consequently, other psychiatric disorders, such as Gilles de la Tourette syndrome or tic disorders were not included in this review. As for sleeping disorder, it was decided to exclude these from the review since sleeping disorders are frequently not viewed as specific medical disorder, but rather as part of a symptom complex of several neuropsychiatric disorders. For a recent review on sleeping disorders in children with neurodevelopmental disorders, see the study by Blackmer and colleagues .Second, strict criteria for methodologic quality of the studies were used for the inclusion and consequently only 29 studies were selected, out of more than 4000 studies that were identified in our initial search. Third, we excluded studies that were not published in English, which might have led to the exclusion of potentially relevant studies.Bearing these limitations in mind, several strong aspects about this systematic review allow us to conclude that a valuable overview of data is provided. First, the methodologic quality and strength of evidence of the various studies has been assessed in a systematic manner by using a standardized set of criteria. This helps to appreciate individual studies in a correct manner. Second, two raters independently assessed the quality of the studies, selected from two databases, with a standardized set of criteria. An additional rater was consulted in case of a difference in scoring by the other two raters. Third, by using a predefined search strategy, the potential for bias was reduced.In conclusion, medical comorbidity in children and adolescents with ASD and ADHD appears to occur in numerous medical areas , 70. ThiAlso, developmental disorders such as autism can be a feature of several underlying genetic syndromes, many of which also entail somatic symptoms. As such, a careful analysis of the combination of ASD and somatic disorders requires an extensive diagnostic scheme to detect such genetic syndromes to consider referral to a clinical geneticist. For a review on this specific topic, see the study by Cohen and colleagues .With respect to research in ASD and ADHD, future studies should not only focus on psychiatric symptoms, but provide a broader evaluation of medical disorders, preferably with longitudinal studies. Likewise, it would also be worth to study a specific group of medical disorders and comorbid ADHD and/or ASD. This may ultimately help to provide a more personalized treatment approach and broaden our insight in etiological aspects of ASD and ADHD.


Background: Children with a diagnosis of attention-deficit hyperactivity disorder (ADHD) have lower cognitive ability and are at risk of adverse educational outcomes; ADHD genetic risks have been found to predict childhood cognitive ability and other neurodevelopmental traits in the general population; thus genetic risks might plausibly also contribute to cognitive ability later in development and to educational underachievement.Methods: We generated ADHD polygenic risk scores in the Avon Longitudinal Study of Parents and Children participants (maximum N: 6928 children and 7280 mothers) based on the results of a discovery clinical sample, a genome-wide association study of 727 cases with ADHD diagnosis and 5081 controls. We tested if ADHD polygenic risk scores were associated with educational outcomes and IQ in adolescents and their mothers.Results: High ADHD polygenic scores in adolescents were associated with worse educational outcomes at Key Stage 3 , reduced odds of sitting Key Stage 5 examinations at age 16–18 years  and lower IQ scores at age 15.5 . Moreover, maternal ADHD polygenic scores were associated with lower maternal educational achievement  and lower maternal IQ .Conclusions: ADHD diagnosis risk alleles impact on functional outcomes in two generations (mother and child) and likely have intergenerational environmental effects. Attention-deficit hyperactivity disorder (ADHD) is the most common childhood neurodevelopmental disorder and is linked to lower cognitive ability,,,ADHD is a highly heritable complex disorder, with twin study estimates of heritability at 76%.The current study aimed to examine if ADHD polygenic risk scores predicted adverse educational and cognitive outcomes in adolescents and adults (in mothers of study children) from the general population and to explore if this association was mediated through IQ scores or through ADHD symptoms in childhood.18 analysed on 502 702 single nucleotide polymorphisms (SNPs). Quality control procedures, ascertainment of these samples and GWAS results have been described in detail previously.The alleles and associated effect sizes selected to be taken forward in order to calculate polygenic risk scores were derived from a case-control UK/Irish ADHD GWAS. This ‘discovery’ study was performed on 727 children aged 4–18 years with a confirmed research and clinical diagnosis of ADHD, and 5 081 population controls from the Wellcome Trust Case Control Consortium–Phase2,http://www.bris.ac.uk/alspac/researchers/data-access/data-dictionary/]. Ethical approval was obtained from the ALSPAC Law and Ethics Committee and the local ethics committees.The Avon Longitudinal Study of Parents and Children (ALSPAC) is a prospective birth cohort which recruited pregnant women with expected delivery dates between April 1991 and December 1992, from Bristol UK; 14 541 pregnant women were initially enrolled, with 14 062 children born. Detailed information on health and development of children and their parents was collected from regular clinic visits and completion of questionnaires. A detailed description of the cohort has been published previously.A total of 9912 ALSPAC children and 10 015 ALSPAC mothers were genotyped on the Illumina HumanHap550-quad and the Illumina Human660W-quad genome-wide SNP genotyping platforms, respectively. Quality control procedure details have been published previously.The discovery sample was selected for this study due to its similarity with the target sample in terms of both ethnicity and geographical location, as well as its robust diagnostic assessment process. Individuals in the target and discovery samples were recruited from geographically nearby regions . An identity by descent (IBD) analysis was conducted using PLINKADHD traits were assessed in ALSPAC when the participants were aged 7 years and 7 months, using the parent-completed Development and Well-Being Assessment (DAWBA).* (highest) to G (lowest). For this analysis, a continuous score (0–483) reflecting capped total points summed over the eight best GCSE grades achieved was employed. Academic performance for the children was assessed at three different points during their education in the UK. First, Key Stage 3 national tests take place in the UK when children are aged 13–14 years and include tests in English, Maths and Science. A continuous score (0–141) reflecting total points summed over all the national tests at Key Stage 3 was used. Second, the General Certificate of Secondary Education (GCSE) examinations are taken when pupils turn 16 years of age in the UK. Pupils study up to 12 subjects (8 on average), some of which (e.g. English and Maths) are compulsory as part of the National Curriculum. The subjects are graded individually on a scale of And week of gestation. The mothers were asked about all the qualifications they had obtained. From the data, a 5-point education scale was obtained, with the following categories: No qualifications/No higher than GCSE ; Vocational qualification; O-Level or equivalent; A-level or equivalent; Teaching or Nursing qualification/University degree.Information on maternal education was collected by questionnaires completed when the mothers were in the 32A subset of ALSPAC mothers completed the Wechsler Abbreviated Scale of Intelligence (WASI),,P < 0.5 was used to select alleles more common in cases than controls from the discovery sample (SNPs in relative linkage equilibrium in the ALSPAC GWAS were first selected). These identified SNPs were used to calculate a polygenic score for each individual in ALSPAC, corresponding to the mean number of score alleles (weighted by the logarithm of the odds ratio) across the set of SNPs. Analysis was performed using PLINK.Polygenic risk scores were calculated separately for ALSPAC children and mothers according to the method described by the International Schizophrenia Consortium (ISC)2 in the full model, as compared with the null model which included sex but not polygenic score. P- values were determined from likelihood ratio tests, which compare the full model with the null model.Multivariate linear regression models were used to test whether standardized polygenic risk scores for ADHD were associated with total IQ and educational outcomes including gender as a covariate. The same analysis was also performed when stratifying children by sex, due to the higher numbers of boys with ADHD. When there was an apparent difference in effect magnitude between boys and girls, a test of interaction was performed by including an interaction term in the model. Logistic regression was employed for categorical variables. The amount of variance explained was calculated as the difference of Nagelkerke pseudo-R,α and β in Sobel–Goodman test is not normally distributed, the standard errors of the indirect effect will not be accurately calculated.,Educational achievement and cognitive ability as measured by IQ scores are strongly correlated, and structural equation modelling (SEM) can incorporate the association of ADHD polygenic risk scores with both outcomes, to unpick pleiotropic and unique relationships with each outcome. The Sobel–Goodman mediation testMultiple mediation, including both IQ and ADHD symptoms as mediators in the model, was performed using Zellner’s seemingly unrelated regression,n = 2942 and 48.9% female, n = 2806) had genetic data and complete DAWBA data assessed at an average age of 7 years and 7 months [standard deviation (SD) 1.7 months]; 114 children had a DSM-IV diagnosis of ADHD (any type) based on the DAWBA. A total of 4958 children from ALSPAC  had genetic data and full-scale IQ data from the WASI assessment at an average age of 15 years and 5 months (SD 3 months). Their mean full-scale IQ was 91.9 (SD 13). In all, 6385 children had both genetic data and Key Stage 3 data, with mean Key Stage 3 score of 106.2 points (SD 24.4), and 6928 children had both genetic data and GCSE data with mean score of 328.2 points at GCSE level (SD 89.9). Of those who sat GCSEs, 2782 did not continue to Key Stage 5 level and 4146 did.A total of 5748 children from ALSPAC  and their mean full-scale IQ was 98.9 (SD 13.9).P = 0.001]. Moreover, the results show an association of ADHD polygenic risk scores with decreased IQ at age 15.5 years  (IJE online).Polygenic risk scores for ADHD were associated with worse adolescent educational outcomes, as indicated by the score achieved at the end of Key Stage 3 as well as by GCSE scores . ADHD po × 10−4] . Sex-strP = 0.005], as measured by the mothers’ self-reported highest qualification obtained and lower maternal IQ  when adjusting for maternal ADHD polygenic scores . Results from the mediation analysis using bootstrapping showed a consistent pattern of results and are presented in IJE online).To explore if the association between children’s ADHD polygenic scores on educational outcomes is mediated through their IQ scores or through their ADHD symptoms in childhood, we performed structural equation modelling using the Sobel-Goodman test. In the first model, including GCSEs results as the outcome and IQ as the mediator, 49% of the effect of ADHD polygenic scores on educational outcomes in adolescents was mediated through IQ . In the P = 0.002] with most of the mediated effect (79%) attributed to IQ (IJE online).A model with both IQ and ADHD symptoms as mediators was also tested. This model supported evidence for an indirect effect ; the Medical Research Council, the Wellcome Trust and Cardiff University [MRC Centre for Neuropsychiatric Genetics and Genomics 079711/Z/06/Z]; the Medical Research Council, the Wellcome Trust and the University of Bristol [core ALSPAC support 102215/2/13/2].The contribution of psychiatric genetic risks to functional outcomes in adulthood has not previously been investigated.High ADHD polygenic scores are associated with worse educational outcomes and lower IQ in adolescents from the general population and in their mothers.ADHD genetic risk impacts on poorer educational and cognitive outcomes in two generations (mother and child) and likely has intergenerational environmental effects.Supplementary DataClick here for additional data file.


Very little is known about the prevalence of ADHD symptoms in Bulimia Nervosa and Binge Eating Disorder and even less in other eating disorders. This knowledge gap is of clinical importance since stimulant treatment is proven effective in Binge Eating Disorder and discussed as a treatment possibility for Bulimia Nervosa. The objective of this study was to explore the prevalence and types of self-reported ADHD symptoms in an unselected group of eating disorder patients assessed in a specialized eating disorder clinic.In total 1165 adults with an eating disorder were assessed with a battery of standardized instruments, for measuring inter alia ADHD screening, demographic variables, eating disorder symptoms and psychiatric comorbidity. Chi-square tests were used for categorical variables and Kruskal-Wallis tests for continuous variables.Almost one third (31.3 %) of the patients scored above the screening cut off indicating a possible ADHD. The highest prevalence rates (35–37 %) were found in Bulimia Nervosa and Anorexia Nervosa bingeing/purging subtype, while Eating Disorder Not Otherwise Specified type 1–4 and Binge Eating Disorder patients reported slightly below average (26–31 %), and Anorexia Nervosa restricting subtype patients even lower (18 %). Presence of binge eating, purging, loss of control over eating and non-anorectic BMI were related to results indicating a possible ADHD. Psychiatric comorbidity correlated to ADHD symptoms without explaining the differences between eating disorder diagnoses.There is a high frequency of ADHD symptoms in patients with binge eating/purging eating disorders that motivates further studies, particularly concerning the effects of ADHD medication. The finding that the frequency of ADHD symptoms in anorexia nervosa with binge eating/purging is as high as in bulimia nervosa highlights the need also for this group. Very little is known about the prevalence of Attention Deficit Hyperactivity Disorder (ADHD) symptoms in Bulimia Nervosa (BN) and Binge Eating Disorder (BED) and even less in other eating disorders (ED) . This knThe lifetime prevalence of ED for females has been estimated to 0.9 % for Anorexia Nervosa (AN), 1.5 % for BN and 3.5 % for BED . In a reFor ADHD, one meta-analysis estimated the prevalence to 5.9–7.1 % for children and adolescents and 5 % for young adults . ADHD isn = 30) of longstanding  ED fulfilled criteria of ADHD with both current and childhood symptoms. In a nationally representative sample, the occurrence of ADHD in young girls was associated with subsequent ED for females and with binging and/or purging behavior but not with restrictive behavior   = 31.89, p = 0.000], inattention trait score (ITS)  and hyperactivity trait score (HTS) .Kruskal-Wallis tests revealed statistically significant differences across ED diagnoses for ASRS trait score , purging , loss of control over the eating  and BMI > 17.5 .When further exploring the association to ED symptoms, ASRS ≥14 was found to be positively related to binge eating  but not for CPRS-anx. (p = 0.245) or CPRS-com. (p = 0.208). Four Mann–Whitney U Tests for CPRS-dep. pairwise comparing AN-R with all bingeing/purging ED groups  revealed no significant differences . This prevalence is high compared to estimates of ADHD frequency in ED in previous studies: 5.3–21 % [In this consecutive series of adults seeking help at a large specialized ED clinic, the ASRS-screener was above cut-off (≥14), indicating a possible ADHD, in almost one third (31.3 %) of the entire patient group n = 116. This pr5.3–21 % , 19, 20.A marked difference was seen in the frequency of ADHD symptoms between the ED diagnoses. The ASRS-screener indicated a possible ADHD about twice as often in BN patients as in AN-R. AN-BP had ASRS-screener levels almost as high as BN, which to our knowledge is not shown before. EDNOS-BP, BED and EDNOS-R patients had intermediate frequencies of ASRS-screener results above the cut-off level (≥14). Although AN-R had a low frequency indicating a possible ADHD in our study (17.6 %), it was still high compared to previous findings of 3 %  and alsoThe analysis of ED symptoms indicated a significant positive relation between ASRS ≥14 and the presence of binge eating/purging behaviors, loss of control over eating and BMI > 17.5, however with small effect sizes limiting the interpretation of these findings. Our results were in accordance with a recent study, including a nationally representative sample, which showed that clinical ADHD was associated with clinical bingeing/purging .Our finding that the ITS had a stronger relationship with ED than the HTS has previously been shown to be the case in adult ADHD where the hyperactivity/impulsivity symptoms are less prominent than among children and adolescents . HoweverThe medium strong correlations between the ASRS trait score and depression, anxiety and obsession-compulsion respectively, estimated with CPRS, are in line with the high psychiatric comorbidity for depression and anxiety in both ADHD  and ED , 11. HowThere were too few males and females with an EDNOS type 5 diagnosis in the study to include them in any meaningful statistical analyses. However, it seems as if the frequency of possible ADHD among men is on the same level as among the bingeing/purging females, while it seems to be much lower than in any other group among the EDNOS type 5 patients.ED and ADHD share many symptoms  and the There is a great need to conduct research aimed at better understanding the nature of the association between ADHD and ED. Because of the methodological limitations, it would also be very useful if this study could be replicated using more detailed assessments of ADHD symptoms in as large a sample as possible.There are cumulating evidence of a good effect on bulimic symptoms when comorbid ADHD is treated with stimulants –29. In aThere are several strengths with this study to mention. First, the cohort constitutes the total intake of adult patients in a single clinic for a certain period of time. Second, the study sample is comparably large. Third, the study sample is recruited during an extended time period (31 months) minimizing confounding from time dependent differences. Fourth, there is no demand for an admission note. Fifth, men are included. Altogether, we suggest these results to be representative for adult patients searching help at a specialized ED clinic.However, there are some limitations of this study to consider. First, an ADHD diagnosis postulate the presence of ADHD symptoms since childhood. The ASRS scale used in the present study only records ADHD symptoms during the last six months, probably resulting in an overestimation of ADHD prevalence. Second, the use of a very short rating scale for ADHD is unlikely to identify the full range of symptoms associated with this condition. Third, the use of web-based self-report instruments made it possible to examine a large cohort of patients. Something that had been difficult had we chosen more time-consuming diagnostic methods. However, this also means that our results suffer from the validity problems that accompany the use of self-report instruments. Fourth, in a help seeking population like the present one there could be a bias to overestimate symptoms. We have not controlled for the possibility that such a bias is unevenly distributed in the different ED diagnoses and thus distorting our results. Fifth, the assessment methods used do not supply information that makes it possible to control for other possible reasons for ADHD-like symptoms, like personality or dissociative disorders, learning disability or medical reasons. Thus, it is not possible to rule out such symptoms as alternative explanations to our results. Sixth, the cross sectional design of the study mean that we cannot establish a causal link between ADHD symptoms and ED. Seventh, there is a shift from restricting to bulimic ED diagnoses and also a symptom shift in ADHD with increasing age, meaning that our results may not be applicable for children and adolescents. Eighth, the number of men were too small for sub group statistics.This prospective study, including a much larger patient cohort than previous studies, supports earlier findings of a high frequency of ADHD symptoms across separate ED diagnoses, especially those with bingeing/purging behaviors. The finding that patients with the bingeing/purging subtype of AN have ASRS-results indicating a possible ADHD on level with BN patients is new and in need of replication. The study also lends further support to recent observations of inattentive ADHD symptoms being more prominent than hyperactivity/impulsivity symptoms in adult female ED patients. Patients with BN, BED, bulimic EDNOS and AN bingeing/purging subtype might benefit from a better understanding of the connections between their ADHD symptoms and their ED. Further studies on the implications for this comorbidity including controlled treatment trials with stimulants for bingeing/purging ED are needed.


Previous cross-sectional research has shown that parents of children with attention deficit hyperactivity disorder (ADHD) have high rates of psychopathology, especially ADHD and depression. However, it is not clear whether different types of parent psychopathology contribute to the course and persistence of ADHD in the child over time. The aim of this two wave study was to investigate if mother self-reported ADHD and depression influence persistence of offspring ADHD and conduct disorder symptom severity in adolescents diagnosed with ADHD in childhood. A sample of 143 males with a confirmed diagnosis of ADHD participated in this study. ADHD and conduct disorder symptoms were assessed at baseline and reassessed 4 years later. The boys in this sample had a mean age of 10.7 years at Time 1  and 13.73 years at Time 2 . Questionnaire measures were used to assess ADHD and depression symptoms in mothers at Time 1. Mother self-reported ADHD was not associated with a change in child ADHD or conduct symptom severity over time. Mother self-reported depression was found to predict an increase in child conduct disorder symptoms, but did not contribute to ADHD symptom levels. This study provides the first evidence that concurrent depression in mothers may be a predictor of worsening conduct disorder symptoms in adolescents with ADHD. It may, therefore, be important to screen for depression in mothers of children with ADHD in clinical practice to tailor interventions accordingly. Attention deficit hyperactivity disorder (ADHD) is a disabling neurodevelopmental disorder that has major adverse consequences for individuals and their families . Whilst Despite its clinical importance, the causes and pathophysiology of ADHD are not well understood. It has been well established that ADHD is a highly familial and heritable disorder with mean heritability estimates of approximately 80 %, which also suggests that non-inherited factors also contribute . The eviParent psychopathology is known to be strongly associated with offspring disorder –10, althWithin samples of children with ADHD, a number of cross-sectional studies, including our own , have deThere is some indication that parental psychopathology may be associated with persistence of ADHD longitudinally; one study found that family history of ADHD was associated with ADHD persistence . WhetherIn the only study to date looking at the long-term outcomes for children with ADHD with depressed mothers, Chronis and colleagues found, as part of an eight-year longitudinal study of 108 families, that the children of mothers with depression have higher risk of developing conduct problems when controlling for baseline conduct severity . This stThese initial studies indicate the potential importance of parental ADHD and depression as markers of ADHD prognosis in adolescence and potentially into adult life, although further work is needed to replicate these findings and investigate the area further. We aimed to address this by building upon previous work, including our own in a clinical sample of children with ADHD . We usedThe sample consisted of 143 males aged 10–17 years [mean age of 13.73 (SD 1.74)] diagnosed with ADHD in childhood, all of whom had participated in a larger genetics study approximately 4 years earlier (Time 1). Mean age at Time 1 was 10.71 years (SD 2.14) with an age range of 6–15 years. Participants were initially recruited from child and adolescent psychiatry and pediatric services in the UK. Each child met diagnostic criteria for ADHD confirmed by research diagnostic interviews at Time 1  , a semi-Information on whether young people had a current prescription for ADHD medication was also obtained. At Time 1, 83 % of the children were treated on ADHD medication and 80 % at Time 2. There was no information collected on any non-pharmacological treatments.Maternal psychopathology was assessed at Time 1 using questionnaire measures. Mothers completed a questionnaire regarding ADHD symptoms in themselves at age 7–11 years (childhood) and in the last 6 months (current), using an 18 item checklist of DSM-5 ADHD symptoms  at Time 1 . As in pMothers also completed a DSM-5 conduct symptom checklist on the presence of conduct disorder symptoms in themselves at age 7–11 years. Symptom presence was rated on a Likert scale from 0 to 3 . Ratings of ‘sometimes’ or ‘often’ were taken to indicate the presence of a symptom which were then summed to calculate a total symptom score of mother self-reported conduct symptoms in childhood.ADHD symptom and conduct symptom change scores were calculated to observe the changes in these symptoms over time. Total symptoms at Time 2 were subtracted from total symptoms at Time 1. Negative scores indicate symptom reduction over time, and positive scores indicate increase over time.Mother self-reported ADHD and depression were considered as predictors using both binary [presence of ADHD diagnosis status (meeting DSM-5 criteria during childhood and current ADHD) and presence of mother depression (using HADS cut-point) and dimensional scores (mother self-reported current ADHD symptoms and depression symptom scores]. Offspring ADHD outcome measures were (1) ADHD diagnosis at Time 2—persistent and remitted ADHD, (2) ADHD change score, and (3) ADHD symptom severity at Time 2. Offspring CD outcome measures were (1) CD change score and (2) CD symptom severity at Time 2.Logistic regression was used to estimate odds ratios and 95 % confidence intervals to predict ADHD persistence in the child at Time 2 in relation to maternal psychopathology. Linear regression was used to estimate differences  in child ADHD and conduct symptom severity scores at Time 2 and change in symptom scores from Time 1 to Time 2 in relation to maternal psychopathology at Time 1. We adjusted for child age, child ADHD and conduct disorder symptoms at Time 1, mother self-reported childhood conduct symptoms, period between Time 1 and Time 2, and ADHD medication status at Time 2 as potential confounders in the final model. All analyses were performed using STATA (version13).Clinical and demographic data were compared between families who took part at both time points and those participants recruited at Time 1 only. There were no differences between these groups in ADHD and conduct symptom severity or prevalence of mother self-reported depression and ADHD at Time 1. In this sample, we found that 19 % (95 % CI 0.13–0.27) of mothers met the study criteria for ADHD and 21 % (95 % CI 0.14–0.28) of mothers met the study criteria for depression. Only 6.6 % of mothers met study criteria for both ADHD and depression. Sociodemographic characteristics of the sample are shown in Table n = 112) of the young people continued to meet full criteria for DSM-5 ADHD diagnosis—persistent ADHD . The remaining 18 % (n = 25) of young people did not meet full diagnostic ADHD criteria at Time 2—remitted ADHD. Although they no longer met criteria for ADHD, these young people still had ADHD symptoms  and 19 young people were still being treated with ADHD medication.At Time 2, 82 % ]. The prevalence of conduct disorder at Time 2 was 53 % . A total of 36 % of young people had developed new onset conduct disorder at Time 2 and 17 % had conduct disorder persisting between both time points. Only 3 % of those with conduct disorder at Time 1 no longer fulfilled symptom criteria at Time 2 .p = 0.80]. There was also no evidence of association between mother self-reported ADHD status and child ADHD symptom severity at Time 2  (Table p = 0.35)  6, 3.78 pβ = 0.11, 95 % CI −0.34, 0.55, p = 0.64) . However, there was a trend towards an association between mother current ADHD symptoms and child conduct symptom severity .With regard to conduct disorder symptoms, there was no evidence of an association between mother self-reported ADHD status and conduct symptom severity at Time 2 ]. It was also found that depression status in mothers did not predict child ADHD severity at Time 2 or ADHD symptom change score , , 7.08, pβ = 0.54, 95 % CI 0.14, 0.93, p = 0.008) (Table p = 0.02)  . Adjusting for baseline medication and oppositional defiant disorder symptoms at Time 1 did not alter the association between mother depression status and child conduct disorder.Several probable confounders were identified which could potentially influence the association between mother self-reported depression and child conduct outcome at Time 2. The period between Time 1 and Time 2, mother childhood conduct disorder symptoms, and ADHD medication status at Time 2 were found to be correlated with mother depression status and child CD outcome at Time 2. After adjusting for child age and the confounders mentioned above, the effect of mother self-reported depression status on child conduct outcome at Time 2 was slightly attenuated, but the association still remained  and mother depression symptoms ].As a separate analysis, we examined to what extent all observed associations changed after adjustment for low social class. Adjusting for low social class had slightly attenuated associations between mother self-reported depression and child conduct symptoms at Time 2 by approximately 6–12 % , and therefore, there was insufficient power to further investigate this. Mothers of children with ADHD are also reported to have higher anxiety symptoms compared to controls [Adults with ADHD are reported to have high rates of comorbid anxiety and depression . It woulcontrols . In thisThis analysis was conducted on a sample of boys, and therefore, we could not investigate if the effect of parental psychopathology on child outcomes would be the same in sample of girls with ADHD. The previous studies have found that girls are more sensitive or vulnerable to effects of maternal depression as they enter adolescence compared to boys –59. The Findings from the present study have important clinical implications. When assessing children with ADHD in clinic, it is important for clinicians to be aware of the high prevalence of parent mental health problems. It may be especially important to screen for depression in mothers and tailor treatment and intervention accordingly. It is also important to consider the multiple impairments or difficulties faced by families, especially if the parent has mental health difficulties . PrelimiOverall, our results suggest that concurrent depression in mothers predicts adverse clinical outcome in terms of conduct disorder symptoms in a sample of boys with ADHD. Further work is needed to understand the processes that contribute to this link, given the global impairment in functioning associated with conduct disorder in ADHD. The study also suggests that the influence of parent psychopathology on longer term outcomes in boys with ADHD may differ by specific parental psychopathology. However, we are not able to test this directly due to our limited sample size, and this needs to be investigated further.


Mental health services are not always good for you. There are some troubling facts to confront such as the increase in the use of diagnostic based approaches and psychotropic medications for children and young people being associated with poorer rather than better outcomes. In this article I will outline some of the evidence around outcome as a result of treatment for young people diagnosed with attention deficit hyperactivity disorder (ADHD) and for those who are prescribed long-term stimulants. I will then discuss clinical approaches that move beyond a focus on symptom management that diagnostic paradigms encourage. This includes clinical models that take account of the diversity of contextual and relational issues that young patients present with and the possibility afforded of engaging in more positive and hopeful therapeutic approaches such as the Relational Awareness Programme (RAP). Mental health services aren’t always good for you. Although over-diagnosis and unnecessary care is recognized as a growing problem across medicine  is also found. Weisz and colleagues  reportedWhitaker  has docuOf particular concern is the increase in the rate of ADHD diagnosis and stimulant prescription to young people. In the USA it is estimated that 11% of children aged between 4 and 17 have been diagnosed with ADHD and between half and two-thirds of these are then prescribed stimulants Sharpe, . In the It requires little intellectual effort to reach the inescapable conclusion that the concept and definition of ADHD is replete with problems around reliability and validity. For example, diagnostic guidelines note that ADHD behaviours may be minimal or absent in a number of settings such as when the person is under close supervision, a novel setting, or engaged in especially interesting (to them) activities Whitely, . Even ifexplains a person’s symptoms and signs. Diagnosis therefore points to causal processes. Making an accurate diagnosis is a technical skill that enables effective matching of treatment to address a specific pathological process. Pseudo-diagnoses like ADHD cannot explain behaviours as there are only “symptoms” that are descriptions (not explanations) of behaviours. Even using the word “symptom” may be problematic, as in medicine “symptoms” usually refers to patients’ suffering/experience as a result of an underlying disease process and is therefore associated in our minds with a medical procedure leading to an explanation for the “symptom”. Consider the following example: If I were to ask the question “what is ADHD?” then it is not possible for me to answer that question by reference to a particular known pathological abnormality. Instead I will have to provide a description, such as ADHD is the presence of the behaviours of hyperactivity, impulsivity, and poor attention . Contrast this with asking the question “what is diabetes?” If I were to answer this question in the same manner by just describing symptoms such as needing to urinate excessively, thirst and fatigue, I could be in deep trouble as a medical practitioner as there are plenty of other conditions that may initially present with these symptoms and diabetes itself may not present with these symptoms in a recognizable way. In order to answer the question “what is diabetes?” I have to refer to its pathology involving abnormalities of sugar metabolism. I would then get independent (to my subjective opinion) empirical data to support or otherwise my hypothesis about what may be “causing” the patient’s described experiences (such as testing the urine and/or blood for levels of glucose). In the rest of medicine therefore, my diagnosis explains and has some causal connection with the behaviours/symptoms that are described. Diagnosis in that context sits in a “technical” explanatory framework. In psychiatry what we are calling diagnosis (such as ADHD) will only describe but is unable to explain.In psychiatry , there is no such thing as diagnosis. In medicine diagnosis is the process of determining which disease or condition caused by ADHD, then a legitimate question to ask is “how do you know that they are caused by ADHD?” The only answer I can give to that question is that I know it’s ADHD because the child is presenting with hyperactivity, impulsivity and poor attention. In other words if we try to use a classification that can only describe in order to explain, we end up with what philosophically is known as a “tautology”. It is troubling when doctors use a diagnosis like ADHD to explain and cannot see this problem of tautological circularity. Furthermore, the idea that a diagnosis like ADHD “explains” behaviours, risks undermining our ability to attend to a whole host of other real-life factors that may have an important role to play in the development of ADHD behaviours in some children; from lack of sleep to witnessing domestic violence, from being the youngest in the classroom to struggling to keep up with the academic demands of school and so on.The problem of using a classification like ADHD to explain an observed set of behaviours (i.e. as a diagnosis) can be illustrated by asking another set of questions. If I was to ask “why” a particular child cannot concentrate, is hyperactive and shows impulsivity and I were to answer that these behaviours are but not diagnostic. As a classification it can have its uses such as recognizing and validating people’s struggles, as well as administrative and communication functions; but only if such a system of classification can be shown to have other advantages .This means that in psychiatry we are mostly working with a system for classification that is descriptive, As ADHD is not a medical diagnosis, but a descriptive classification, we have no empirical method for defining “caseness”. The definition of what qualifies as a case is thus arbitrary and depends on the standards employed by the diagnoser, influenced by whatever the prevailing ideology concerning diagnosis they have been exposed to. As a result we cannot eliminate wide variation in “diagnostic” practice or come to any valid conclusion about what percentage of the population could be considered as “over” or “under” diagnosed.As ADHD is not a medical diagnosis it is not surprising that there has been a failure to find any specific and/or characteristic biological abnormality such as characteristic neuroanatomical, genetic or neurotransmitter abnormalities , could not find support for continuing superiority of medication regardless of initial severity  has little impact on outcomes, whereas relational and contextual aspects of care are crucial  that comes back to them from a caregiver is experienced as rewarding in some way. Seeking emotional energy is a better way of describing what children do than seeking attention.Relationship dynamics are then built up through these emotional energy ties that family members have to each other and over time this becomes a dynamic between any group of people who spend extended lengths of time together.Over time we each develop roles within any group and these roles tend not to be ones that we have consciously chosen but rather the emotional, relational dynamic “settling” into a certain recognizable pattern that everybody in the group (often unconsciously) recognizes. For example, it is a well-known phenomenon that if you have a partner, one of you will end up being the one preoccupied with tidying up, another one may be preoccupied with sorting out the bills or getting children ready in the morning, and so on. Many then find that even if you want the roles to change, it doesn’t feel “right” when you do. So, for example, if you are the one who is concerned about keeping the house tidy and you yearn for your partner to also do this, when they do it, somehow they never seem to be able to do it in the “right” way and so you have to re-do it to what you consider to be the correct standard. This is a bit like each family member having a “script” that they follow which identifies their role and should any member come along with a new script that changes their usual role, it throws everybody else out because it doesn’t seem “natural”. There is thus a powerful and usually unrecognized emotional force from other members pushing anybody who goes “off script” back towards the script that everybody recognizes. So if a child occupies the role of say “the troublemaker”, family members will often assume that this child is in some way involved whenever trouble is happening.The concept of “Emotion WARS” then forms the background starting point in moving toward changing the emotional dynamics in the “relationship script” by helping parents, teachers and others in caring roles focus on relationship building by moving away from emotional energy reinforcing negatives and toward reinforcing positives. They then learn skills for dealing with issues such as rules, consequences, and their own emotional resilience. For our RAP group workshop model we have used a programme consisting of four 2½-h groups spread out over 2 months between the first and last groups. We have developed an e-learning platform which contains all the resources, including the PowerPoint slides, narrations, exercises and detailed advice on setting up and running the group to enable other practitioners to develop and run groups in their locality. Parents and carers of children with “challenging” behaviour (regardless of diagnosis) are invited. In November 2014 we conducted an evaluation of the outcomes from these groups, as we had outcome data from using the Outcome Rating Scale , rated a clinically significant improvement and/or rated their child as being in the clinically non-significant range, by the last group. These figures should of course be viewed with caution as this was not part of a research project and therefore there was no control group. However, they offer some promise as many attendees reported going for multiple other interventions with their children prior to trying this group and the findings compare favourably with the real world setting outcomes found in the research quoted earlier. One of the most common feedback comments from participants who attended with a successful outcome is that what changed most for them was their “attitude” to their child; which became more understanding and co-operative.RAP is a relationally based intervention. In some senses this mirrors what the evidence discussed earlier in this article finds, which is that therapy essentially takes place in the negotiated space of meanings that makes up the alliance. Therefore, I believe, we should be careful not to become too reliant on one set of ideas or method. What matches the rhythms of significance and meaning for each family may be different. As a result it’s useful to have a whole variety of ideas to draw from. Thus, possible therapeutic strategies are as numerous as there are people and families wanting help. As the ADHD label is unable to offer much more than a vague description, the specifics of each case differ; meaning that finding helpful therapeutic strategies may similarly differ depending on the family , adding a daily multi-vitamin and mineral supplement and an EPA rich essential fatty acid, and balance the diet by removing excess sugars and dairy products.Enable your children to get plenty of opportunities for exercise (particularly outdoors) including chances for unstructured and unsupervised active play.Notice your child’s strengths and support and encourage these in a positive direction. Use clear and consistent consequences for unwanted behaviour and work hard to stick to these and not give in . Try not to get drawn into arguments, which often feed negativity to everyone.Find opportunities to do things together as a family on a regular basis. Like all relationships we have to continue “working” on our relationships with our children (year after year after year after …).Talk to each other, but more importantly listen to each other (not the same thing). Try and understand your child’s point of view and help them understand yours. Create regular opportunities for you to communicate, listen and try and understand what’s on each of your minds.The following “pitfalls”, leading to therapeutic strategies failing, are also worth keeping in mind:With some interventions, unwanted behaviours can get worse before they start to improve, resulting in parents giving up on the strategy prematurely.Setbacks are an inevitable part of any recovery process. Hopelessness can creep in and with it a sense of failure and a loss of confidence in the ability to bring about lasting change. When the inevitable setback occurs, remember it’s very common and don’t give up at this point.If we have unrealistic expectations of our children, then we will feel disappointed with them no matter what changes.Children are often clever enough to spot opportunities that arise from inconsistencies in order to further their own desires, for example, by playing one parent off another.This is where issues such as inconsistency can become a potentially serious obstacle to progress. In a situation where the parental couple have separated, it is vital for parents to put any continuing animosity towards one another to one side and keep the child out of any arguments.For example, if a parent had an unhappy relationship with their own parents resulting in them feeling hate or fear towards that parent, they may act with their own children in a way that is designed to avoid this happening to them, resulting in trouble enforcing boundaries with their own children.In this “drama” a parent becomes infuriated with the child’s behaviour, imposes some sort of punishment (anger), they then calm down and feel that their punishment was unduly harsh (guilt), as a result they try to repair some of the damage they feel they have done and so may give some sort of treat or comfort to their child (reparation). The child may learn that any consequences imposed may be withdrawn and, indeed, may be followed by some sort of reward.We are exposed to constant messages telling us how dangerous the outside world is, particularly for children. The subsequent desire to protect our children from the perceived dangers of the world may hamper children’s capacity to develop the resilience they may need to cope in later life.This can be a change in any member of the family (see above about family scripts). Change usually causes a certain amount of anxiety and fear of the unknown, not just for the individual but also other family members.As the old African saying reminds us “it takes a village to raise a child”. Raising children demands a lot from parents both physically and mentally, and given the pressures they face, they need trusted partners, friends and other family members to provide emotional and practical support.Another feature of modern life is how busy and time stretched we are. With so many things to do and such little time to do them we may feel stressed and this often impacts on children.Everybody reacts differently to trauma . For some, trauma may lead them to feel preoccupied, constantly worrying about their safety and the safety of others and they may present with poor concentration, as things like school work will be of limited importance to them. Others may have developed the psychological defence of “being on the go”; by constantly doing things it keeps their minds away from thinking about what has happened and what may happen in the future.ADHD is a cultural construct. It is often argued that the use of categorical constructs like ADHD enables the study of aetiology, treatment and prognosis. Evidence outlined above demonstrates that far from enabling any advancement of knowledge or clinical practice, it has created an illusion of progress and resulted in exposure of possibly millions of children and young people to unnecessary and potentially harmful medications. It has spurred on liberal use of stimulant medication, despite the lack of evidence for improved long term outcomes resulting from this. ADHD is an example of the “MacDonaldization” of children’s mental health where marketing and commodification of our anxieties about failure  has triumphed over science and good ethics Timimi, . The con


P = 2.51e-08) for the overall score of BRIEF. The association analyses for each component of executive function found this locus was more associated with inhibit and monitor components. Further principle component analysis and confirmatory factor analysis provided an ADHD-specific executive function pattern including inhibit and monitor factors. SNP rs852004 was mainly associated with the Behavioral Regulation factor. Meanwhile, we found the significant locus was associated with ADHD symptom. The Behavioral Regulation factor mediated its effect on ADHD symptom. Functional magnetic resonance imaging (fMRI) analyses further showed evidence that this variant affected the activity of inhibition control related brain regions. It provided new insights for the genetic basis of executive function in ADHD.As a childhood-onset psychiatric disorder, attention deficit hyperactivity disorder (ADHD) is complicated by phenotypic and genetic heterogeneity. Lifelong executive function deficits in ADHD are described in many literatures and have been proposed as endophenotypes of ADHD. However, its genetic basis is still elusive. In this study, we performed a genome-wide association study of executive function, rated with Behavioral Rating Inventory of Executive Function (BRIEF), in ADHD children. We identified one significant variant (rs852004,  The genetic epidemiological studies revealed gene variants constituted the primary etiology of ADHD, with a heritability estimated to be 0.762. Candidate genes were involved in the biosynthesis, release, transmission and metabolism of neurotransmitters3, while genome-wide association studies7 suggested genes contributing to the brain development. The complex genetic architecture of ADHD is still far from fully illustrated8.Attention deficit hyperactivity disorder (ADHD) is a common psychiatric disorder characterized by age-inappropriate deficiency in sustained attention and/or hyperactive, impulsive behaviors10. Executive function (EF) is a high order cognitive function that provides people the capacity to change and adjust behaviors according to the shifting demands of the complex environment11. Executive dysfunction has been found in many psychiatric disorders, such as bipolar disorder12, depression13, schizophrenia14, autism15 and ADHD16. Candidate genes involved in the neurotransmitter system, including dopaminergic, noradrenergic, serotonergic and cholinergic, have been reported to be associated with some component of executive functions17. Yang et al. identified one significant locus for inhibition in ADHD by using genome-wide association study18.One of the reasons for the complexity of ADHD is that it is a heterogeneous disorder. The same clinical presentation of inattention, hyperactivity and impulsivity may have different etiological contribution. Identification of the genetic contributions to ADHD is likely complicated by phenotypic and genetic heterogeneity, low penetrance, and limited statistical power. One way to enhance power for genetic discovery is to reduce heterogeneity by use of endophenotypes. Presently, the most common endophenotypes under consideration are neuropsychological markers of executive functionIn this study, we performed a genome-wide association analysis on the global score of executive function using the Behavior Rating Inventory of Executive Function (BRIEF) and further analyzed the association of the significant locus with each component of executive function and ADHD symptoms. Furthermore, we analyzed the function of associated locus via neuroimaging study in human and its underlying molecular mechanism contributing to brain function and behavior. The findings may provide new insights into the pathological mechanisms of ADHD.We collected three dimensional symptoms for the patients, namely inattention (CDISatt), hyperactivity-impulsivity (CDIShi) and overall assessment . We calculated the correlations between the BRIEF scales and three symptom traits  = −11.84 ) located in 6q25.1. The A allele carriers had smaller BRIEF score, which means better executive function. Regional plot for this locus was shown in Fig. Firstly, we analyzed the association of SNPs with the global score of BRIEF. We identified one significant SNP , we further performed confirmatory factor analysis (CFA) for the two candidate models. The Model A is based on the definition of BRIEF indexes: one group constituted of IB, SFT and ECTRL, the other group constituted of INIT, WM, PO, OM and MONI 4. Association analysis for the significant SNP rs852004 with ADHD symptoms was conducted to further validate the contribution of the significant SNP rs852004. Among the 550 samples, 533 samples have both symptoms data and genotype data for SNP rs852004. The analysis showed it was significantly associated with the total assessment , which denoted the ADHD symptom of A carriers was better.SNP rs852004 was not significant in our Chinese ADHD case-control GWAS (19 to bootstrap the sampling distribution of the indirect effect (where the indirect effect is the reduction in the strength of the SNP/symptom association that is due to the executive function). The indirect effect of rs852004 on ADHD total symptom score  through each BRIEF scale was shown in Supplementary Table Furthermore, we examined the role of each BRIEF scale as a mediator to mediate the association between rs852004 with the ADHD symptom. We used the model 4 in PROCESSP < 0.01, cluster size above 202 voxels). The interaction of diagnosis and genotype was found in six clusters, including right orbitofrontal cortex, dorsal striatum, insula, lingual cortex, left inferior frontal cortex, inferior temporal cortex . In term of the simple effect of rs852004, compared to G homozygote, no increased or reduced ReHo was discovered after multiple comparison in either ADHD or control group.Among 50 ADHD patients, 42 are G homozygotes for rs852004; among 66 control children, 57 are G homozygotes for rs852004. Compared with healthy controls, reduced Regional Homogeneity (ReHo) was uncovered in ADHD in dorsolateral prefrontal cortex, medial prefrontal cortex and increased ReHo in thalamus, anterior cingulate cortex, and anterior insular cortex  are expressed in various brain regions, with the highest transcript level in cerebellar cortex (RMND1), thalamus (C6orf211 and ZBTB2), and inferior olivary nucleus (ESR1). We found significant association between rs852004 with these genes separately in thalamus , cerebellar cortex , frontal cortex . All the eQTL data were summarized in Table The significant locus we identified was within the upstream of ESR1, RMND1, ZBTB2 and downstream of CCDC170 and C6orf211 , Emotional Regulation factor , and Metacognition factor . The Model C we established based on the association result of rs852004 was similar with their 3-factor model although the Monitor was not parsed in our model. Based on this model, SNP rs852004 was mainly associated with Behavioral Regulation factor. Remarkably, in our model, Behavioral Regulation factor is more correlated with Metacognition factor, but not Emotional Regulation factor as Gioia et al.’s 3-factor model23. One possible explanation for this is disorder-specific executive function profile. This model is more consistent with Barkley’s view of executive function in ADHD24: inhibitory control having a unique and separable role in executive function; inhibition is more primary and plays an underlying role that enables other functions including working memory, emotional regulation and goal directed analysis and synthesis in problem-solving. Furthermore, in ADHD, the underlying “enable” role of inhibition may have more apparent effect on metacognition factor, including working memory, monitor and plan/organize. The indirect mediation effect of rs852004 on ADHD symptom through each BRIEF scale  and thalamus (RMND1) which constitutes dorsolateral prefrontal striatum circuit, which is the basis of inhibition, including response inhibition and interference inhibition37. We hypothesized that SNP rs852004 influenced these genes expression in consequence to affect the executive function, especially inhibition, and ADHD symptoms.SNP rs852004 and its LD-proxy rs6908732 were suggested to be associated with schizophreniaThe detailed molecular mechanism of the significant locus on inhibition related brain function and behavior need further validation study. In consideration of the complexity of cognition and behavior, it’s likely that more genes are still needed to be discovered in larger samples, and more aspects of executive function should be discussed.38. Those comorbidities with major neurological or psychiatric disorders including epilepsy, schizophrenia, pervasive development disorder, and mental retardation (IQ < 70) were excluded.Totally, 550 subjects finished the Behavior Rating Inventory of Executive Function (BRIEF)  aged between 6 and 16 years (average 9.77 ± 2.44 years). All participants in this study were recruited from the Child and Adolescent Psychiatric Outpatient Department of Peking University Sixth Hospital. All cases met DSM-IV ADHD diagnostic criteria. A clinical diagnosis was first made by a senior child and adolescent psychiatrist based on the ADHD Rating Scale-IV (ADHD-RS-IV) completed by parents (and teacher when available), and then confirmed by semi-structured interview using the Chinese version of the Clinical Diagnostic Interview ScaleA total of 50 ADHD patients  and 66 control children  aged between 8 and 16 years were enrolled from the Child and Adolescent Psychiatric Outpatient Department of Peking University Sixth Hospital in this section. All the participants were right-handed. The ADHD samples are part of the above ADHD samples for BRIEF. The controls were also interviewed to ensure that they were free of any Axis I psychiatric disorders. This study was approved by Institutional Review Board of Peking University Sixth Hospital and written informed consent was signed by parents.i.e. Initiate (INIT), Working Memory (WM), Plan/Organize (PO), Organization of Materials (OM) and Monitor (MONI); while Behavior Regulation Index (BRI) comprising of three subscales, i.e. Inhibit (IB), Emotional Control (ECTRL) and Shift (SFT)39. The score of each subscale equals to the sum of the scores of all items belonged to that subscale; the scores of two indexes equals to the sum of the scores of all subscales belonged to the index. The score of the Global Executive Composite equals to the sum of the scores of the two indexes. All these traits and their name abbreviation used in this study were shown in Table 40. CDISatt denotes the inattention symptom score, CDIShi denotes the hyperactivity-impulsivity symptom score, and CDISall denotes the sum of CDISatt score and CDIShi score.We assessed the executive function using BRIEF, an 86-item questionnaire designed for parents of children aged 5–18 years to assess executive function behaviors. In the questionnaire, the parent responds whether their child exhibits problems with specific behaviors: Never, Sometimes or Often, scored as 1, 2, or 3, respectively. The questionnaire includes two domains: Metacognition Index (MI) comprising of five subscales, 42. Tracy-Widom test was employed to detect significant eigenvectors (P < 0.05). Only the first eigenvector (eigenvector 1) was significant, which was used as a covariate in the subsequent statistical analysis. When controlling for the quality of SNPs, we removed SNPs if (1) per-SNP call rate <98%, (2) Hardy-Weinberg equilibrium test P < 0.001, (3) MAF < 1%. Totally, 644,166 autosomal SNPs were analyzed in 547 ADHD patients after quality control.Genomic DNA was extracted from peripheral blood using Omega DNA extraction Kit . Genotypes were obtained using the Affymetrix6.0 array at CapitalBio Ltd. (Beijing) using the standard Affymetrix protocol. The Affymetrix6.0 array included 906,600 SNP probes. After mapping them to SNPs with #rs, 653,428 SNPs were left. For quality control, the individuals (1) with per-individual autosomal heterozygosity >5 s.d. away from the mean, (2) having no age or IQ information, (3) per-individual call rate <95% and (4) with relatives having genome identity PI_HAT ≥ 0.185 were removed. Then, the remaining samples were assessed for population stratification using Principal Component Analysis (PCA) implemented in EIGENSOFT4.2Resting-state fMRI data acquisition, preprocessing and quality control detailed is described in the supplementary material.43 with age, IQ, sex and eigenvector 1 of PCA as covariates. Two-sided P < 5 × 10−8 was considered as genome-wide significance. We used MACH-admix 1.044 to impute non-genotyped SNPs using the ASN data  from the 1000 Genomes Project Integrated Phase 1 Release45 as the reference panel. Imputed SNPs with squared correlation between imputed and true genotypes (rsq) <0.6 or SNPs with MAF < 0.01 were removed. Association analysis after imputation was done using mach2qtl46.Association analysis for each quantitative trait was conducted using an additive model in linear regression in PLINK2/df value, the root mean square error of approximation (RMSEA), the Comparative Fit Index (CFI), Tucker-Lewis Index (TLI) and standardized root mean-square residual (SRMR). Smaller χ2/df, RMSEA and SRMR values and larger CFI and TLI values indicate a better fit.All scores of the eight scales of BRIEF were normalized prior the principle component analysis (PCA) and confirmatory factor analysis (CFA). The PCA was conducted in SPSS. CFA for the several candidate models of BRIEF was conducted using AMOS. The maximum likelihood method was used. Fit of all models was evaluated using several indexes, including the χ47 and the inclusive threshold for each voxel was set to P < 0.01. The following statistic analysis was conducted in SPM (http://www.fil.ion.ucl.ac.uk/spm/software/spm12/). A T test was applied to identify the differences between ADHD and control, and then a full factor model was built to test the main effect of the interaction effect of genotype and diagnosis, with mean framewise displacement (FD)48, gender, age, cohort used as covariates. Post hoc t tests were performed to further investigate the effect of genotype in different diagnostic groups (ADHD or control). The cluster-level analysis threshold was set to P < 0.01 determined by Monte Carlo simulation correction which was also utilized for multiple comparison correction, and recalculated the kernel of smoothness.Individual ReHo map was generated in DPABI by calculating the Kendall coefficient of concordance (KCC) of the time series of a given voxel with those of its neighbors (26 voxels) in a voxel-wise wayr2 > = 0.75) using the 1000 Genomes Project ASN population data. The regulatory features related with these SNPs were searched in rVarBase49, HaploReg50 and RoadMap WashU EpiGenome Browser51. The eQTL data were searched in GTEx Portal52, SCAN53, seeQTL54, SMRI human prefrontal cortex eQTL data21, and BRAINEAC (http://caprica.genetics.kcl.ac.uk/BRAINEAC/).To explore the affected gene expression, we got the SNPs in LD with the significant SNP (The datasets generated during the current study are available from the corresponding author on reasonable request.The study was approved by the Institutional Review Board of Peking University Sixth Hospital and carried out in accordance with relevant guidelines and regulations. Written informed consent was obtained from parents of the ADHD probands and controls.Supplementary Material


Our study is an analysis of multiple publications involving assessing the comparable efficacy and tolerability of six interventions, which are lisdexamfetamine dimesylate (LDX), atomoxetine (ATX), methylphenidate (MPH), clonidine hydrochloride (CLON), guanfacine extended release (GXR), and bupropion, for young patients (6–18 years old) suffering from attention deficit hyperactivity disorder (ADHD).A conventional meta-analysis (MA) was performed to give direct comparisons and a network meta-analysis (NMA) was used to show the combination of direct and indirect evidence. Ranking preference for all the interventions under a certain outcome was given by the surface of cumulative ranking curve area (SUCRA).Overall, 15,025 participants from 73 studies were involved in our analysis. In the pairwise MA, LDX was associated with less withdrawal than ATX for lack of efficacy. MPH showed less effectiveness than LDX according to ADHD Rating Scale score. Based on the analysis of our NMA, significant results of efficacy that LDX is a competitive drug were observed when evaluating LDX in comparison with other drugs except for CLON. ATX and GXR presented higher rates of abdominal pain morbidity versus inactive treatment.The stimulants LDX and MPH are still highly recommended because they are highly effective and are tolerated well by patients. Among the non-stimulants, CLON can be taken into consideration for its appreciable effectiveness and tolerability. ATX and GXR can be seen as moderate choices. Attention deficit hyperactivity disorder (ADHD) is a common kind of psychological behavior disorder that occurs in approximately 5% of children or adolescents (6–18 years of age) worldwide . It is a2-adrenergic agonist developed to reduce and delay the release and has recently been used in combination with psychostimulants to treat ADHD (2A-adrenoceptor agonist for the treatment of ADHD. The efficacy of guanfacine extended release (GXR) is considered to be among first-line treatments for ADHD . Seven outcomes have been considered, including ADHD Rating Scale (ADHD-RS), all cause withdrawal, withdrawal due to adverse event, withdrawal due to lack of efficacy, nausea, abdominal pain, and fatigue.A systematic search was conducted in PubMed, Embase, Cochrane library, and CNKI , aiming to retrieve randomized controlled trials (RCTs) related to drug therapy in children and juveniles with ADHD. We used the following key words: “randomized controlled trial,” “attention deficit hyperactivity disorder” (including synonyms), and “drug therapy.” The cited articles of references including RCTs, systematic reviews or meta-analyses were also searched manually as supplementary material. Ethical approval was not needed for this study.Type of study: mostly RCTs of a minimum of 3-week duration will be included in this review.Type of participants: children and adolescents aged between 6 and 18 who meet Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) criteria for ADHD.Type of interventions: studies involving direct comparison with one drug therapy against another or against placebo will be included. All target interventions are ATX, CLON, GXR, BUP, LDX, and MPH.Type of outcome measures: the efficacy is evaluated by ADHD-RS as a continuous score. And the adverse effects (as a dichotomous outcome) for tolerability are all cause withdrawals, withdraw due to adverse event, withdrawal due to lack of efficacy, nausea, abdominal pain, or fatigue for tolerability. Weight loss is not included because there is limited outcome on it.We extracted baseline data and evaluated the risk of bias, including selection bias, performance bias, detection bias and other bias, by the means of random sequence generation, allocation concealment, blinding, incomplete outcome data, and selective reporting. The assessment tool came from Cochrane Handbook (version 5.1.0) for RCTs. Data of interest were blinding, durations, diagnostic criteria, treatment, age of patients, number of patients, and assessment criteria for patients’ conditions.Q test (I2 test (P > 0.05 or I2 < 50%). Otherwise, a random-effects model was used.Conventional meta-analysis (MA) was performed by STATA 12.0 software, which gave us direct comparisons among these drugs, in the forms of the mean deviation (MD) with the corresponding 95% confidence interval (CI) for the primary outcomes of ADHD-RS, and the pooled odds ratios (ORs) with 95% CI for the secondary outcomes of tolerability. Cochran’s Q test  and the  separately. Ranking preference for all the interventions under a certain outcome was given by the surface of the SUCRA, the value of which was 1 for the best and 0 for the worst.P-value was a significant parameter to assess whether there was consistency in comparing direct and indirect evidence, and P < 0.05 showed a statistical inconsistency. The degree of consistency was illustrated by color in the heat plot.There are five domains are bias due to (1) the randomization process, (2) deviations from intended interventions, (3) missing outcome data, (4) measurement of the outcome, and (5) selection of the reported results . We usedFigure The results of the direct MA were shown in Table Bayesian models allowed for more refined estimates. Comparisons without direct connection were compared indirectly through Bayesian NMA. Available data from NMA was recorded in Tables For adverse effects, including nausea, abdominal pain and fatigue, the results presented further reinforced initial estimates. There was less occurrence of nausea in the groups treated with GXR, MPH and placebo than those with ATX . Statistically significant data was available in comparing morbidity of abdominal pain. A statistical decrease of morbidity was observed in LDX versus other drugs except for CLON . ATX and GXR presented higher morbidity of abdominal pain versus inactive treatment . MPH presented less abdominal pain than GXR . Similarly, ATX and GXR presented more fatigue than placebo  and MPH resulted in less fatigue than ATX and GXR .The probability of being the best treatment was derived from SUCRA. The result was displayed in Figures The symmetry of the “comparison adjusted” funnel plots in Figure This comprehensive NMA was conducted to compare the efficacy and tolerability of all interventions used to treat young ADHD patients. Our NMA study gave a comprehensive evaluation that included direct and indirect evidence extracted from previous studies. This NMA’s results indicated that the statistical differences between all interventions were compared successfully and their ranking orders under different criteria were determined, respectively. Therefore, it is possible for us to find the optimal treatment option by taking all the outcomes into account.via changing the daily dosage  It is difficult for us to exclude publication bias completely, especially for ADHD-RS and all-cause withdrawal. This may be a result of small sample size and lack of direct comparison between some therapies, such as GXR versus CLON, or CLON versus BUP. (2) Most of the studies compared active treatment to placebo and only a handful of comparative effectiveness studies. (3) Differences in samples, such as mean age, gender ratio, and growth background also affect the accuracy of our NMA. Thus, in order to take all the limitations mentioned above into consideration, better-designed RCT studies should be performed.In summary, according to the results obtained from our NMA, the stimulants LDX and MPH are still highly recommended because they are highly efficacious and well tolerated by patients. Among the non-stimulants, CLON should be taken into consideration for its appreciable effectiveness and tolerability. ATX and GXR can be seen as moderate choices. We failed to evaluate BUP because of the lack of enhanced evidence. Even though this study provides some guidance for the effectiveness and safety of various medications, clinicians still need to use their professional judgment in assessing the benefits with the efficacy and reliability profile of the therapy, as well as patients’ features and preferences in order to make final treatment decisions.Conception or design of the work: RL and ZM. Data acquisition, analysis, and interpretation: FY. Drafting the work: RL and ZM. Revising article critically for important intellectual content: SH. Final approval of the version to be published: all authors.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.