Professor Edmund Sonuga-Barke
Genetics and endophenotypes
The final day of EUNETHYDIS 2018 opened with a symposium on genetics and endophenotypes in ADHD, chaired by Professor Jan Buitelaar (Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands). Professor Anita Thapar (Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, UK) provided an update on ADHD genetics in the first presentation, and highlighted that genetic study designs generally revolve around two styles – the traditional indirect statistically inferred studies (e.g. twin studies), and direct genomic assessments looking at common gene variants and rare variants. The latter has been of more interest in recent years.
Professor Thapar put forward several of her thoughts on genetic testing in ADHD. She noted that common variants are currently too weakly predictive, and that with rare mutations (if these are causal and if clinical implications are possible), clinical evaluations are needed. She proposed that although rare mutations can currently be used in screening for mild intellectual disability and autism, there may be a potential for use in ADHD in the future.1
When looking at using genetic discoveries to test environmental risk factors, a recent paper by Rice and colleagues was noted, which looked at the idea of maternal smoking during pregnancy.2 This review of studies suggested that it is unlikely that maternal smoking in pregnancy has a substantial causal effect on ADHD or conduct problems.2
Professor Thapar emphasised that, in her opinion, rigorous testing is required to discover causal inference, and no one single design is sufficient – methods should be combined to assess causality.
Professor Thapar concluded the presentation by looking to the future, as we begin to move from genes to biology, looking at epidemiology and causal mechanisms, and disaggregating phenotype, subphenotypes and stratification.
In the second presentation of the symposium, Professor Barbara Franke (Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands) examined endophenotypes in ADHD. She began by mapping out potential pathways from gene to disease – starting with the gene, through biochemical processes and cell function, through to regional brain morphology, followed by brain unit function, into behaviour/behavioural traits leading to disease symptoms.3
It was noted that strict criteria exist for defining an “endophenotype”; it must be a heritable trait; segregate with disease in families; be state-independent; be associated with disease in the population; be present at higher rate in affected families than in the population; and reliable measurement must be possible.4
Professor Franke gave an overview of the ENIGMA Consortium, which is exploring the disease-related architecture of the human brain, and within which exists the ENIGMA ADHD Working Group. One of the projects from the ADHD Working Group found that total brain volume was slightly smaller in people with ADHD, and that nearly all subcortical regions measured (most notably the amygdala) are slightly smaller in ADHD.5 Professor Franke also presented top-line results from a second project, the publication of which is currently under review.
Professor Franke concluded by saying that, in her opinion, research into endophenotypes is important to define the biological mechanisms leading from gene to disease. Endophenotypes for ADHD can be identified at the brain-image level; however, the genetic overlap between ADHD and currently available brain measures is still limited.
In the final presentation of the first session, Professor Edmund Sonuga-Barke (Department of Child & Adolescent Psychiatry, King’s College London, London, UK) discussed the gene–environment interplay in ADHD, and asked if there is a role for the family environment. Within normative environments, he suggested that, in his experience, shared genes largely determine ADHD, rather than shared rearing environments, and that any links between ADHD and rearing environments may be due to passive or evocative gene–environment correlations.
In discussing gene–environment interactions, Professor Sonuga-Barke noted a study that found that a 5-HTTLPR (serotonin-transporter–linked polymorphic region) genotype moderated the relationship between family conflict/cohesion and inattentive symptoms;6 however, he went on to note that caution should be exercised in the application of these studies, as in his opinion, the results for gene–environment interactions in ADHD are very inconsistent and replication is rare.
Professor Sonuga-Barke also examined cases of extreme deprivation and development by looking at an adoption study of profoundly deprived children from Romanian orphanages pre-1990s.7 In this study, 165 children were on a severely restricted diet with little social or cognitive stimulation for a period of 1–43 months, before being adopted into nurturing and supportive families; 52 UK adoptees with no history of deprivation were followed-up at 6, 11 and 15 years of age, and in young adulthood.7 The study found that rates of ADHD in those with <6 months of deprivation (low-deprivation group) were similar to the general population in adolescence (5.6%) and adulthood (3.8%), whereas those with >6 months of deprivation were nearly four- (19%) and over seven- (29.3%) times more likely to meet criteria than the low-deprivation group.7
Professor Sonuga-Barke: “There is controversy surrounding environmental effects in ADHD … and it is hard to effectively disentangle these from the impact of genetics.”
Dr Corina Greven
World Federation of ADHD: Is there a positive side in ADHD?
This symposium was chaired by Professor Luis Augusto Rohde (Federal University of Rio Grande do Sul, Porto Alegre, Brazil) and Professor Manfred Gerlach (Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University of Würzburg, Würzburg, Germany), and started with PhD student, Ms Jane Sedgwick (MRC Social, Genetic and Developmental Psychiatry Centre, King’s College London, London, UK), discussing her currently unpublished qualitative investigation of successful people with ADHD. She indicated that the main aim of this study was to investigate strengths, attributes or positive aspects that could mediate or compensate for ADHD-related deficits or impairments in adults with ADHD.
The next speaker was PhD student Ms Trine Arildskov (Department of Clinical Medicine, Aarhus University, Aarhus, Denmark), who presented preliminary results from her PhD research, which is investigating whether children with ADHD traits confer an advantage during a timed search in a novel environment.
Following a change of programme, Dr Corina Greven (Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands) was next to speak, and discussed her research into the positive side of ADHD. Dr Greven began by discussing whether the “low extreme” of ADHD can be adaptive or maladaptive. She then presented data which showed that when ADHD traits were assessed using the Strengths and Weaknesses of ADHD Symptoms and Normal Behaviour (SWAN) questionnaire, individuals who were described as having “low extreme” ADHD traits showed fewer internalising and externalising behavioural problems, improved cognitive performance, and more positive behaviours and home environmental outcomes compared with “high extreme” or “average” levels of ADHD.8
The final speaker of this session was Professor Rohde, who presented current data on the association between ADHD and entrepreneurship. Professor Rohde stated that there are few studies which have studied this association, but directed the audience to a recent publication that has discussed entrepreneurship in relation to clinical characteristics of adults with ADHD.9 Professor Rohde discussed the results of this study, and emphasised that, in his opinion, although the negative symptoms of ADHD cannot be dismissed, a diagnosis of ADHD may not always be associated with a negative effect in professional life.
This symposium concluded with a discussion and questions from the audience. One audience member queried whether “low ADHD traits” is the most appropriate term and whether these individuals should instead be described as “hyper-attentive”. The session ended with Dr Greven stating that we need to look for strengths and weaknesses at the individual level in those with ADHD.
Dr Greven: “… this is a topic I’m passionate about … we need to also focus on the strengths of ADHD.”
Professor Rohde: “When you assess ADHD as a categorical disorder, it is associated with high entrepreneurship.”
Professor Guilherme Polanczyk
Early intervention and prevention
In a symposium chaired by Professor Manfred Döpfner (Department of Psychiatry and Psychotherapy of Childhood and Adolescence, University of Cologne, Cologne, Germany), Dr Amy Goodwin (Centre for Brain and Cognitive Development, Birkbeck, University of London, London, UK) gave a presentation on attention-control training for infants with a family history of ADHD. She provided an overview of the background and design of the unpublished INTERSTAARS study – a multisite, randomised controlled trial to investigate the potential efficacy of an early attention-control training intervention in 10–14-month-old infants (N=50) with a first-degree family member with ADHD, and an increased familial likelihood for ADHD.10 The INTERSTAARS trial is ongoing, with recruitment expected to be completed in September 2018 and data collection expected by the end of 2018.
Dr Goodwin noted that there is limited evidence for effects of cognitive training in childhood,11,12 but she suggested that this may be because the intervention did not occur early enough in previously conducted trials. Some parents have already provided very positive feedback about the study, saying that they have enjoyed the sessions and enjoyed seeing their baby’s reactions to the tasks. Dr Goodwin concluded by noting that positive results have been seen in early intervention in those with high risk of autism, and that the researchers are looking forward to seeing results in those with high risk of ADHD.13,14
Professor Guilherme Polanczyk (Department of Psychiatry, University of São Paulo Medical School, São Paulo, Brazil) then looked at the presentation of and intervention in pre-school ADHD. He presented data from a study that is currently in preparation for publication, which investigated correlations between irritability and ADHD symptoms, and between social difficulties and ADHD symptoms, as well as some preliminary data from the Medication and Parent Training Study for Preschoolers with ADHD (MAPPA).
Professor Polanczyk felt that we could focus on these early interventions to ensure a strong foundation for future development for the child. He also explained that, in his opinion, it is at this early stage that interactions within the family are just being established, and therefore may be more amenable to change, and that ideally, children of this age will be less severely impaired compared with older children.
Completing this symposium on early intervention, Professor Margaret Thompson (University of Southampton, Southampton, UK) discussed parental training for pre-school children at risk of ADHD. The range of factors/constructs/processes within the “parenting” sphere that she believes should be addressed in parent-led interventions were outlined, including those ranging from early parent–infant interaction and building that relationship, to child social skills and behavioural control, and consistency/long-term maintenance. Results from a meta-analysis showed that these factors are present in parent-led interventions,15 and that some success has been seen when looking at parent-rated outcomes, but not when children were independently assessed for ADHD symptoms.16
Considering specialist ADHD programmes versus generic programmes, Professor Thompson noted that results from two studies have yet to find any superiority of specialist programmes over generic programmes.17,18 She hypothesised that there may be several reasons for this non-superiority, including: the possibility that specialist programmes confer long-term effectiveness that we do not yet have data for, and the fact that there is currently uncertainty over which components should be included in the specialist programmes.
Professor Thompson concluded her presentation by looking at the question of what more needs to be done in the future to understand the potential effectiveness and efficacy of parenting as a treatment.
Professor Polanczyk: “We need to make sure that any new treatments or interventions are fully incorporated by health services.”
Professor Sven Bölte
Health-related quality of life and functioning/impairment in ADHD
This keynote talk was chaired by Professor Buitelaar and presented by Professor Sven Bölte (Department of Women’s and Children’s Health [KBH], Karolinska Institutet, Stockholm, Sweden). Professor Bölte began his talk by saying that he felt a balanced and more informative view of ADHD should take health-related quality of life (HRQoL) into account, and stated that there is no mention of HRQoL in either the Diagnostic and Statistical Manual of Mental Disorders – 5th Edition (DSM-5TM)19 or the World Health Organization Revision of the International Statistical Classification of Diseases and Related Health Problems (ICD-11).20 He further emphasised that, in his opinion, these diagnostic tools only have a crude acknowledgement of functioning.
Professor Bölte admitted that HRQoL is hard to define but stated that, in his opinion, life satisfaction, well-being and happiness were important in defining HRQoL. He then went on to discuss functioning and explained that, in his view, this is a complex interaction between abilities and disabilities and how they affect an individual’s health, as well as how contextual and personal factors affect their environment. Professor Bölte then listed reasons why he felt it was important to pay more attention to HRQoL and functioning (e.g. to lessen stigmatisation, to gain a better description of an individual’s difficulties in real life, and because this provides an opportunity to emphasise an individual’s strengths).
Professor Bölte indicated that there are issues with measuring HRQoL and that there may be differences between self-reported HRQoL and proxy-reported HRQoL.21 He also suggested that HRQoL may change over time and may change following pharmacotherapy,22 so emphasised that better measures are required to assess HRQoL over time. Professor Bölte then went on to discuss the International Classification of Functioning, Disability and Health (ICF) and presented his recent publication on the consensus for ICF Core Sets for ADHD.23 He also directed the audience to material describing how ICF Core Sets can be used in clinical practice (https://www.icf-core-sets.org/).
Professor Bölte was then asked questions by the audience, and there was a discussion on the cost-effectiveness of measuring HRQoL and a suggestion that future studies could investigate the short- versus long-term utility of measuring HRQoL and functioning.
Professor Bölte: “HRQoL is still a little under the surface … but [poor HRQoL] is why people seek support [from services] and not necessarily because of symptoms.”
Professor Jan Buitelaar
ADHD and overlap with neurodevelopmental disorders
The final symposium of EUNETHYDIS 2018 began with a presentation by Professor Bölte looking at ADHD and co-existing neurodevelopmental disorders such as intellectual disability, tic disorders, learning disorders, language disorders, and autism spectrum disorder (ASD).24 He took this opportunity to provide his view on the overall key message of the published data across overlapping psychiatric disorders.
Before looking at the disorders themselves, Professor Bölte presented his own opinion of how neurodevelopmental disorders should be defined. He felt that it should be an “umbrella term”, inclusive of conditions arising from qualitative alterations or extreme variations in the maturation, architecture and functioning of the developing brain. In Professor Bölte’s view, neurodevelopmental disorders should be characterised by cognitive challenges, e.g. in executive function, top-down processing, social cognition, motor/phonological awareness and learning. He explained that they have heterogeneous aetiologies and presentation and, importantly, a high degree of overlap.
Professor Bölte went on to describe his view that the overlap between these disorders may be a result of the co-existence and co-occurrence of one or more psychiatric disorder(s), as multiple diagnoses beyond chance or expectancy, sharing phenotypes, endophenotypes, aetiologies and/or pathways. He went on to explain that assessing overlap may itself present issues, e.g. potential differences between clinical samples and populations, heterogeneity of study results and age.
In the second presentation of the symposium, Professor Emily Simonoff (Department of Child & Adolescent Psychiatry, King’s College London, London, UK) gave her opinions on the topic of ADHD and intellectual disability. She explained that, in her view, there may be two groups of patients with this overlap: those with mild intellectual disability (psychosocial adversity, strong family loading – seen in the majority of cases) and those with severe/profound intellectual disability (no increased psychosocial adversity, low level of familial recurrence, single gene conditions, increased copy number variants, increased homozygosity – seen in a minority of cases).
Professor Simonoff went on to list the syndromes that she feels may be most strongly associated with ADHD, in order of prevalence of overlap. These were: velocardiofacial syndrome (22Q-deletion syndrome), Noonan syndrome, Fragile X syndrome, neurofibromatosis, tuberous sclerosis and Smith-Magenis syndrome.
She then presented results from a 2003 study in which 90 children (aged 4–17 years) with ADHD and low IQ received the same dose regimen of methylphenidate in three independent, placebo-controlled studies. Both teachers and parents reported improvements in attention, overactivity and conduct problems in patients who received methylphenidate compared with placebo; however, the clinical response rate appeared lower than in typically developing children with ADHD.25 Professor Simonoff went on to present results from a more recent 16-week, randomised, double-blind, placebo-controlled trial in 122 children, which reported improvement with methylphenidate compared with placebo; however, the effect-size difference of the Conners ADHD Index was very small.26 She noted that there is a paucity of trials of ADHD treatment in individuals with intellectual disorder, and that further trials are warranted.
Professor Simonoff summarised that, in her view, ADHD is severely under-researched in people with intellectual disability and that ADHD in severe/profound intellectual disability is also likely under-recognised. Looking to the future, she concluded that intervention research will not only benefit patients, but will provide a window into underpinning mechanisms and new objective measures that may help to estimate intervention effects.
In the final presentation of this symposium, Professor Buitelaar looked at ASD and ADHD, and biomarker discovery in the EU-AIMS Longitudinal European Autism Project (LEAP) study.27 Professor Buitelaar outlined the need for the development of biomarkers in ADHD/ADHD with ASD, emphasising that, in his view, this could benefit both patients and clinicians.
The remainder of the presentation discussed the EU-AIMS LEAP study, which is a large, multicentre, multidisciplinary, observational study on biomarkers for ASD.27 The study enrolled 437 children and adults with ASD, and 300 controls, from six centres in four European countries (age range: 6–30 years; IQ: 50–148).27 Results showed there was variation in both the core ASD symptom severity and in commonly co-occurring psychiatric symptoms, which were systematically associated with gender, age and IQ.27 However, this variation by age and gender was dependent on whether the ratings were reported by the clinician, the parent or the patient, which could have implications for establishing stratification biomarkers.27
Professor Buitelaar noted that the protocol was developed in consultation with the EMEA to ensure that if any significant biomarkers were found, they would be recognised and properly validated.
Professor Buitelaar: “I feel that the most important challenge we face is moving from ‘symptoms’ to ‘biology’.”
Professor David Coghill
The final session of EUNETHYDIS 2018 concluded with three leading speakers in the field providing their views on the future of ADHD. Professor Rohde said he felt that the heterogeneity of the disease should be reduced, and that there is a need to better characterise the phenotype of adult ADHD. He also said that more should be learned about the difference between persistent and late-onset ADHD. Professor Rohde highlighted that he thought that in the future, more studies will integrate new technology and social media to better understand ADHD.
Professor Tobias Banaschewski (Central Institute of Mental Health, Mannheim, Germany) described his view of future treatment issues in ADHD, and indicated that further long-term studies on efficacy and effectiveness of ADHD treatment should be conducted, as well as studies on treatment adherence. He also said that real-world outcomes could be a future focus, and that any future studies could also investigate the mechanisms underlying non-pharmacological treatments. Professor Banaschewski also highlighted that more studies should investigate both the possibility of preventing ADHD and treatment strategies for pre-school–aged children. Professor Banaschewski suggested that biomarkers may be useful in developing personalised treatment approaches for ADHD.
Professor Philip Asherson (King’s College London and Maudsley Hospital, London, UK) began his final presentation by saying that although the field has learned a lot about ADHD, he felt that there are still some areas which could improve. He indicated that services for adult ADHD have grown but that, in his opinion, adult ADHD should not be limited to specialised services, as it is too common a disease; he added that in the future, he would like to see adult ADHD also being treated in primary care services. Professor Asherson said he hoped there would be more research into the genetics of ADHD, and that future experiments should be well designed to explore causality.
Professor David Coghill (Department of Paediatrics and Psychiatry, University of Melbourne, Melbourne, Australia) then provided his closing remarks, saying that EUNETHYDIS 2018 had been a wonderful congress. He thanked the speakers and delegates, as well as the sponsors. Professor Coghill thanked Professor Asherson for organising the programme, and for the animated discussion and debate throughout the congress.
Professor Rohde: “We need to better characterise the phenotype of ADHD.”
Professor Asherson: “I don’t know if we’re good at predicting who will have late-onset ADHD … and who will have subthreshold ADHD when they are younger.”
Disclaimer: The views expressed here are the views of the presenting physicians and not those of Takeda
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- Rice F, Langley K, Woodford C, et al. Identifying the contribution of prenatal risk factors to offspring development and psychopathology: what designs to use and a critique of literature on maternal smoking and stress in pregnancy. Dev Psychopathol 2018; 3: 1107-1128.
- Klein M, Onnink M, van Donkelaar M, et al. Brain imaging genetics in ADHD and beyond – mapping pathways from gene to disorder at different levels of complexity. Neurosci Biobehav Rev 2017; 80: 115-155.
- Gottesman II, Gould TD. The endophenotype concept in psychiatry: etymology and strategic intentions. Am J Psychiatry 2003; 160: 636-645.
- Hoogman M, Bralten J, Hibar DP, et al. Subcortical brain volume differences in participants with attention deficit hyperactivity disorder in children and adults: a cross-sectional mega-analysis. Lancet Psychiatry 2017; 4: 310-319.
- Elmore AL, Nigg JT, Friderici KH, et al. Does 5HTTLPR genotype moderate the association of family environment with child attention-deficit hyperactivity disorder symptomatology? J Clin Child Adolesc Psychol 2016; 45: 348-360.
- Kennedy M, Kreppner J, Knights N, et al. Early severe institutional deprivation is associated with a persistent variant of adult attention-deficit/hyperactivity disorder: clinical presentation, developmental continuities and life circumstances in the English and Romanian Adoptees study. J Child Psychol Psychiatry 2016; 57: 1113-1125.
- Greven CU, Merwood A, van der Meer JM, et al. The opposite end of the attention deficit hyperactivity disorder continuum: genetic and environmental aetiologies of extremely low ADHD traits. J Child Psychol Psychiatry 2016; 57: 523-531.
- Antshel KM. Attention deficit/hyperactivity disorder (ADHD) and entrepreneurship. Acad Manage Perspect 2018; 32.
- Goodwin A, Salomone S, Bolton P, et al. Attention training for infants at familial risk of ADHD (INTERSTAARS): study protocol for a randomised controlled trial. Trials 2016; 17: 608.
- Sonuga-Barke EJ, Brandeis D, Cortese S, et al. Nonpharmacological interventions for ADHD: systematic review and meta-analyses of randomized controlled trials of dietary and psychological treatments. Am J Psychiatry 2013; 170: 275-289.
- Cortese S, Ferrin M, Brandeis D, et al. Cognitive training for attention-deficit/hyperactivity disorder: meta-analysis of clinical and neuropsychological outcomes from randomized controlled trials. J Am Acad Child Adolesc Psychiatry 2015; 54: 164-174.
- Green J, Pickles A, Pasco G, et al. Randomised trial of a parent-mediated intervention for infants at high risk for autism: longitudinal outcomes to age 3 years. J Child Psychol Psychiatry 2017; 58: 1330-1340.
- Jones EJH, Dawson G, Kelly J, et al. Parent-delivered early intervention in infants at risk for ASD: effects on electrophysiological and habituation measures of social attention. Autism Res 2017; 10: 961-972.
- Kaminski JW, Valle LA, Filene JH, et al. A meta-analytic review of components associated with parent training program effectiveness. J Abnorm Child Psychol 2008; 36: 567-589.
- Rimestad ML, Lambek R, Zacher Christiansen H, et al. Short- and long-term effects of parent training for preschool children with or at risk of ADHD: a systematic review and meta-analysis. J Atten Disord 2016; Epub ahead of print.
- Abikoff HB, Thompson M, Laver-Bradbury C, et al. Parent training for preschool ADHD: a randomized controlled trial of specialized and generic programs. J Child Psychol Psychiatry 2015; 56: 618-631.
- Sonuga-Barke EJS, Barton J, Daley D, et al. A comparison of the clinical effectiveness and cost of specialised individually delivered parent training for preschool attention-deficit/hyperactivity disorder and a generic, group-based programme: a multi-centre, randomised controlled trial of the New Forest Parenting Programme versus Incredible Years. Eur Child Adolesc Psychiatry 2018; 27: 797-809.
- American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. 2013.
- ICD-11. World Health Organization ICD-11 for Mortality and Morbidity Statistics. 2018. Available at: https://icd.who.int/browse11/l-m/en#/http://id.who.int/icd/entity/821852937. Last accessed September 2018.
- Galloway H, Newman E. Is there a difference between child self-ratings and parent proxy-ratings of the quality of life of children with a diagnosis of attention-deficit hyperactivity disorder (ADHD)? A systematic review of the literature. Atten Defic Hyperact Disord 2017; 9: 11-29.
- Coghill DR, Banaschewski T, Soutullo C, et al. Systematic review of quality of life and functional outcomes in randomized placebo-controlled studies of medications for attention-deficit/hyperactivity disorder. Eur Child Adolesc Psychiatry 2017; 26: 1283-1307.
- Bölte S, Mahdi S, Coghill D, et al. Standardised assessment for functioning in ADHD: consensus on the ICF Core Sets for ADHD. Eur Child Adolesc Psychiatry 2018; Epub ahead of print.
- Franke B, Michelini G, Asherson P, et al. Live fast, die young? A review on the developmental trajectories of ADHD across the lifespan. Eur Neuropsychopharmacol 2018; Epub ahead of print.
- Aman MG, Buican B, Arnold LE. Methylphenidate treatment in children with borderline IQ and mental retardation: analysis of three aggregated studies. J Child Adolesc Psychopharmacol 2003; 13: 29-40.
- Simonoff E, Taylor E, Baird G, et al. Randomized controlled double-blind trial of optimal dose methylphenidate in children and adolescents with severe attention deficit hyperactivity disorder and intellectual disability. J Child Psychol Psychiatry 2013; 54: 527-535.
- Charman T, Loth E, Tillmann J, et al. The EU-AIMS Longitudinal European Autism Project (LEAP): clinical characterisation. Mol Autism 2017; 8: 27.