Professor Henrik Larsson
Long-term treatment outcomes – what have we learnt from pharmaco-epidemiological studies?
In the first symposium of Day 3, chaired by Professor Jeffrey Newcorn (Mount Sinai Medical Center, New York City, NY, USA), Professor Henrik Larsson (Karolinska Institutet, Solna, Sweden) began by discussing results from pharmaco-epidemiological studies using datasets in Sweden. He stated that although randomised controlled trials have shown the beneficial effects of ADHD medication in the short term, they are less informative about the effects of these medications in the real world and the associated long-term effects. Professor Larsson then described what he felt were the benefits of pharmaco-epidemiological studies (e.g. large sample sizes, long time scales and information on outcomes relevant to public health, such as criminality and suicide). Professor Larsson emphasised that, in his opinion, using a within-individual study design (i.e. exploring the outcome rate in the same individual during periods on and off medication) is important when conducting pharmaco-epidemiological studies. He then presented results from a number of Swedish pharmaco-epidemiological studies, which have explored the short-term benefits, the short-term risks and the long-term effects of ADHD medication using national registries available in Sweden. Professor Larsson indicated that there is evidence to suggest that ADHD medication may have a protective effect against criminality, motor vehicle accidents and suicidal behaviour in the short term.1-3 Similar results were presented for long-term use of these medications, which showed that ADHD medication use for longer periods of time demonstrated protectiveness against substance use and depression.4,5 Professor Larsson concluded that although these pharmaco-epidemiological studies suggest that there are long-term benefits of taking ADHD medication, more research is required, with clever study designs and statistical approaches; he also suggested that future research should include heterogeneity of effects to account for comorbidity, age and polypharmacy.
The second talk of the symposium was presented by Professor Ian Wong (Department of Pharmacology and Pharmacy, The University of Hong Kong, Pok Fu Lam, Hong Kong), who began by discussing recently published results on the worldwide prescription rates of ADHD medication in children and adults.6 Professor Wong echoed Professor Larsson’s thoughts on the benefits of pharmaco-epidemiological studies, and presented findings from his own studies, which have used data from Hong Kong registries. He highlighted that individuals who use ADHD medication are at a lower risk for injuries,7 and that pharmaco-epidemiological studies have provided evidence to suggest that methylphenidate (MPH) may not increase the risk of suicidal or psychotic behaviour.8,9 Professor Wong concluded that using large medical record databases could provide a powerful tool in evaluating the use of ADHD medications, and that increased collaboration between different study groups should be encouraged, as this could help develop new methodological research approaches.
Professor Hans-Christoph Steinhausen (Centre for Child and Adolescent Mental Health, Copenhagen, Denmark) began the final presentation of this symposium by first highlighting results from a study which showed that prescription rates of ADHD medication increased in Denmark from 1996 to 2010.10 Professor Steinhausen then presented data from a large representative Danish dataset, which showed that the concern that children taking MPH (and other drugs) over long periods of time could be at risk of developing cancer is not substantiated.11 He also showed that there is evidence to suggest that in terms of clinical implications, pharmaco-epidemiological studies have shown that there is less substance-use disorder in those patients who receive MPH.12 Professor Steinhausen then gave an insight into his most recent, but currently unpublished, research, which has used pharmaco-epidemiological studies in a Danish cohort to investigate the effect of ADHD medication on the risk of crime. When concluding, Professor Steinhausen summarised that medication has a long-term impact on various psychological outcomes, and indicated that he felt specific ADHD medication may lay a foundation for protective mechanisms in some individuals with ADHD.
Following the talks, the presenters discussed their opinions on the benefits of using Scandinavian datasets versus those available in Hong Kong. It was pointed out that although the available datasets are rich in the Hong Kong studies, data on criminality and education are not available, which is a key strength of the Scandinavian studies. One audience member highlighted that although pharmaco-epidemiological studies are good for “big-picture effects”, we also need to look at the effects of age and psychiatric comorbidities in these studies. The session ended with one clinician in the audience requesting that the presenters compile the results of these studies into one review article so that these data are accessible to the working clinician.
Professor Larsson: “Studies on the effects of poly-pharmacy are entirely important and currently understudied.”
Professor Wong: “Most clinical trials focus on the core symptoms [of ADHD] … we need pharmaco-epidemiological studies as they measure what is happening in real life … so we need both to give two sides of the story.”
Professor Steinhausen: “Using ADHD medication is one of the most successful stories in childhood psychiatry, so I think we can be a bit proud of that.”
Professor David Heal
Making it happen: ADHD guidelines in clinical practice
(This symposium was initiated, organised and funded by Shire, now part of Takeda)
The second industry-sponsored symposium of the meeting was chaired by Dr David Bull (London, UK), who introduced an in-depth discussion of four of the recently updated ADHD guidelines from the UK13, Canada14, Germany15 and Spain.16
The symposium opened with each panel member (Ms Jen Lewis-Neill [Lancashire NHS Foundation Trust, Accrington, UK], Professor Sam Chang [Department of Psychiatry, University of Calgary, Alberta, Canada], Professor Manfred Döpfner [Department of Psychiatry and Psychotherapy of Childhood and Adolescence, University of Cologne, Cologne, Germany] and Professor Toni Ramos-Quiroga [Department of Psychiatry, Val d’Hebron University Hospital, Barcelona, Spain]) providing a quick-fire summary of the updated guidelines from their respective country. During the panel’s overview of the key recommendations, a couple of important items were noted. Firstly, across both the National Institute of Health and Care Excellence (NICE) and Canadian ADHD Resource Alliance (CADDRA) guidelines, there is an emphasis for giving each drug an ‘adequate’ dose – i.e. ensuring that as much as possible is done to optimise treatment with one agent before moving onto the next, as recommended by the guidelines.13,14 Secondly, both the CADDRA and German guidelines place an emphasis on the importance of the psychosocial aspects of treatment.14,15 Professor Ramos-Quiroga noted that, for the first time, adult ADHD was covered in the Spanish guidelines.16
Following this brief overview of the guidelines, Professor David Heal (Department of Pharmacy & Pharmacology, University of Bath, Bath, UK) gave a presentation entitled “How can pharmacology help determine treatment choice in ADHD”, which provided an overview of the pharmacology of ADHD medications and how it may impact on the way clinicians treat patients. Professor Heal highlighted that the recently updated guidelines now typically recommend stimulants as the first-line therapy (or one of the first-line therapies) across the available pharmacological interventions for ADHD.13-16 He concluded with his opinion that untreated ADHD has far-reaching adverse consequences for those with the disorder, their family, and even the community as a whole.
For the final section of the symposium, Dr Bull led a direct question-and-answer panel discussion with the panel members, eliciting answers to questions relating to implementation and uptake of the guidelines nationally.
Q) Since the updates have been published, what has the uptake been locally?
A) Generally, across the four countries, uptake was noted to be very good, although the German updates have only recently been published so they are still to be fully established. Ms Lewis-Neill noted that in the UK, specialist services show a good acceptance of the NICE update, but those in general psychiatry may require more training and education (training sessions have been well attended).
Q) What are the details of the Spanish regional incentivisation for implementation of guidelines?
A) Professor Ramos-Quiroga explained that areas with greater rates of guideline implementation received increased government funding.
Q) Could guidance bodies do more to advertise and encourage the use of their guidelines?
A) The common themes noted between panel members included development of tools to assist in implementation of the guidelines (such as the toolkit available through CADDRA; caddra.ca), physical distribution of the guidelines (e.g. on a USB drive), provision of training sessions/programmes for those who require it, and setting up infrastructure that can be easily updated each time the guidelines change.
Q) What can we, as healthcare professionals, do to encourage implementation of the guidelines?
A) Professor Ramos-Quiroga stated his desire to have the Spanish guidelines summarised down to two pages and sent to every psychiatrist in Spain. Professor Döpfner noted two barriers to implementation that needed to be addressed in Germany: issues with reimbursement from insurance companies and time restrictions. Ms Lewis-Neill listed three points: 1) using it as a bargaining tool for further financial resourcing; 2) encouragement to ensure that all healthcare professionals stay up to date with not only their own age group of interest, but also others, to help with the transition of patients between services; and 3) that nurses are an untapped resource in many countries. Professor Chang said that he would like to have wider distribution of the Canadian pictorial representation of the ADHD treatment algorithm, which makes it simple to talk with patients about what their treatment plan will involve.
Q) How much should patients be involved?
A) The panel all agreed that patients need to be involved as much as possible, and also proposed extending this involvement to their immediate families, and in some cases even teachers.
Dr Bull concluded the symposium by asking the panel members for key take-home messages for the implementation of guidelines. Professor Ramos-Quiroga said that we have the knowledge – we know what is necessary – we just need to tell everyone we know and distribute that knowledge, and Professor Döpfner added that we also need to develop and deliver tools to help implement this shared knowledge. Professor Chang noted that guidelines are essentially structures, and we need to ensure that all doctors are supported by these evidence-based structures. Ms Lewis-Neill emphasised the importance for those with an understanding of the updated guidelines to support their peers with less of an understanding.
Professor Heal: “We are trying to fine-tune the most complex machine on the planet – the human brain – so don’t be surprised if it takes time and effort to optimise treatment.”
The panel (L–R): Professor Hans-Christoph Steinhausen, Dr Kai Syng Tan, Ms Andrea Bilbow, Professor Margaret Weiss, Professor Edmund Sonuga-Barke
Perceptions of ADHD – best friend or worst enemy
This lively discussion was chaired by Dr Duncan Manders (Child and Adolescent Mental Health Services, NHS Lothian, Edinburgh, UK) and included: Professor Edmund Sonuga-Barke (Department of Child & Adolescent Psychiatry, King’s College London, London, UK), Professor Margaret Weiss (Department of Psychiatry, University of British Columbia, Vancouver, Canada) and Professor Hans-Christoph Steinhausen (Centre for Child and Adolescent Mental Health, Copenhagen, Denmark), who are all child psychiatrists with research interests in ADHD; Dr Kai Syng Tan (Department of Social Genetic & Developmental Psychiatry, King’s College London, London, UK), who is an artist with ADHD; and Ms Andrea Bilbow, OBE (President, ADHD Europe), who is the founder of the National Attention Deficit Disorder Information and Support Service (ADDIS; www.addiss.co.uk). The roundtable discussion began with each participant explaining their experience of ADHD and what ADHD means to them. Professor Steinhausen opened the discussion by explaining that the understanding of ADHD has dramatically changed since the 1970s and that although we now have an increase in the number of services, we still have a long way to go. The participants provided real-world examples of their experience with ADHD and/or patients they had encountered with ADHD. The participants highlighted that because ADHD is classed as a “disorder”, this implies it has no advantages, and Professor Weiss stated that it is necessary to funnel patients with ADHD so they can work on their strengths and not simply focus on their limitations. Ms Bilbow expressed her view that school stifles individuals with ADHD and that the educational system for those with ADHD needs to change. She said that she encourages parents to invest in out-of-school activities so that children with ADHD can build their self-esteem if there have been failings at school. The participants agreed that ADHD can present some individuals with certain “gifts”, which Dr Tan agreed has allowed her to pursue a career in the arts. However, it was made clear that although some individuals ‘benefit’ from their ADHD and can achieve success on an individual level, the disorder is not without suffering and impairment for some. Professor Sonuga-Barke summarised this by saying that “ADHD can be a fickle friend and a persistent enemy”.
The discussion was then opened to the audience and there were discussions on the evolutionary purpose of ADHD, with the idea being raised that as individuals with ADHD can become hyper-focused, they can become workaholics if they have a career they are passionate about. This resonated with Ms Bilbow and Dr Tan, as they said they find it very difficult to “switch off” outside of work. There was also discussion on how “impairment is a societal construct” and that individuals who have ADHD often try to adapt to a lifestyle that society wants; Professor Steinhausen highlighted that this is true for many psychiatric disorders. The discussion ended on a positive note with the suggestion that individuals with ADHD have had to develop resilience to cope with their disorder, and there was debate about what “resilience” actually means. One audience member indicated that in his 30 years as a clinical psychiatrist, he found his ADHD clinic to be the most relaxed and that although his patients could admit their limitations (e.g. forgetfulness and disorganisation), they always managed to smile about it, which could be defined as resilience. The concluding remark from Dr Manders was that the title of this discussion should have been “Perceptions of ADHD – best friend and worst enemy”, as it is clear that there are both positive and negative aspects of ADHD.
Ms Bilbow: “We need to provide an educational system for ADHD, as society would benefit so much from these people in the future.”
Professor Andreas Reif
Transition of ADHD patients from childhood into adulthood
(This symposium was sponsored by Medice)
This symposium was chaired by Professor Tobias Banaschewski (Central Institute of Mental Health, Mannheim, Germany), and focused on the transitioning of patients with ADHD from a clinical and neurobiological perspective. Professor Andreas Reif (Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital Frankfurt, Frankfurt am Main, Germany) opened the session by first discussing transitioning from a clinical perspective. Professor Reif began by presenting his currently unpublished data on the trajectories for ADHD symptoms across age, and indicated that the syndromatic appearance of ADHD changed over the lifespan with a reduction in hyperactive symptoms and an increase in inattentive symptoms from childhood to adulthood.17 Professor Reif then highlighted that ADHD can be a persistent condition in adulthood and that it is clinically important to consider the psychiatric comorbidities and impairments associated with persistent ADHD. Professor Reif also directed the audience to a review article that illustrated the lifespan course of childhood-onset ADHD,18 and echoed opinions raised during the first symposium regarding the protective effect that ADHD medication seems to confer against some of the negative outcomes of adult ADHD.1-4 Professor Reif indicated that his ongoing work includes examining psychiatric comorbidities with ADHD across the ages and also the prevalence of adult ADHD in trauma victims. He stated that biological transitioning from childhood to adulthood is very different from the process of transitioning from Child and Adolescent Mental Health Services to Adult Mental Health Services, and that in his experience, although many individuals drop out of the system during this time period, they often come back to treatment later; however, he feels that it would be better to provide continuous treatment for these individuals. He suggested that child and adult psychiatrists could learn a lot from one another, and presented his suggestions on transitioning of patients with ADHD. Finally, Professor Reif directed the audience to “MiND the gap” (https://mind-the-gap.live/), which is a scientific blog of several European Union-funded multicentre projects on developmental psychiatry.
Professor Barbara Franke (Donders Centre for Neuroscience, Nijmegen, The Netherlands) then discussed transitioning of ADHD patients from a neurobiological perspective, and what ultimately leads ADHD to persist into adulthood. Professor Franke began by highlighting that ADHD is a highly heritable disorder.19 She then discussed results from meta-analyses and genetic risk factors for ADHD in childhood and adulthood, and discussed results from neuroimaging. In summary, she stated that there are differences in brain anatomy, connectivity and function between children and adults with ADHD and that, in her opinion, different mechanisms contribute to remission in ADHD across different brain regions. Professor Franke then highlighted that she is currently investigating the regions of genetic association between children and adults with ADHD, and highlighted her recent publication on the developmental trajectories of ADHD across the lifespan.20 Professor Franke concluded that by using genome-wide association studies, we are able to find new biological processes associated with ADHD as well as confirm what we already know. Professor Franke finished by directing the audience to ENIGMA (http://enigma.ini.usc.edu/), which is a consortium of >40 working groups that share their protocols, as she feels that ‘team science’ is the future.
The symposium was then opened to the audience and it was queried how close we are to using imaging and genetics to confirm a clinician’s diagnosis of ADHD. Professor Reif and Professor Franke felt that although these methodologies are consistently providing new data, there are lots of caveats, as they provide little specificity and many of these genetic risk factors associated with ADHD are also observed in other psychiatric conditions. Professor Franke concluded that although we are making progress in this field of research, we are finding not only answers but also new questions.
Professor Reif: “… there is still poor transition from child to adult services … we need structural solutions for each country.”
Professor Franke: “… [ADHD] is very heritable but there is no ‘ADHD gene’ … there are multiple genetic variants … and different patients [with ADHD] have different combinations of different genes.”
Dr Mary Solanto
Implementing cognitive behavioural therapy for adult ADHD
In this parallel session, Dr Mary Solanto (Developmental and Behavioral Pediatrics, Cohen Children’s Medical Center, New York City, NY, USA; Hofstra Northwell School of Medicine, Long Island, NY, USA) presented her experience in how she and her colleagues conducted a programme focusing on implementing cognitive behavioural therapy (CBT) in adult patients with ADHD in New York. They wanted to create a programme that was practical, “real”, and easy to assimilate; one that would teach new self-management skills and other behaviours to the point where they become habitual, all the while addressing impairing self-attributions. They aimed to do this by teaching explicit skills, contingent self-reinforcement, visualisation of long-term rewards of present behaviour, and traditional CBT to address demoralisation, anxiety and perfectionism. This was achieved by both in-session exercises and home-based exercises, which were then discussed within the next session.
The leaders of the sessions met with patients in groups of 6–10 for 12 sessions of 2 hours each, where they would review the home exercise, present new material, conduct the in-session exercise and review the upcoming home exercise.
In-session exercises included: learning to break down complicated tasks, creating weekly schedules, setting up a filing system, planning a project, etc. Home exercises included activities such as prioritising and scheduling a task list into days of the week, planning projects using a flow-chart, completing one procrastinated task and self-reinforcing from it.
Although the programme leaders were present to ensure the sessions ran smoothly, they couldn’t just do this as though teaching from a script, as they also had to act as a mentor and facilitator to discuss any issues that arose leading to things like non-completion of home exercises. Therefore, the leaders had to be prepared for many different eventualities and excuses by participants.
Dr Solanto concluded her session by outlining the topics included in the programme. Following an introductory session to explain how the sessions would work, the rest of the sessions with the patients focused on time management (five sessions), organisation (three sessions) and planning (two sessions). There was then one final session wrapping up the programme, providing a summation of the learnings and having a final look at future planning.
Dr Solanto: “‘Mantras’ were repeated with participants over and over again to help internalise these ideas.”
Dr Corina Greven
ADHD mindfulness-based interventions and the wandering mind
Dr Corina Greven (Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands) began this breakout session by discussing the history of mindfulness, and presented data from a meta-analysis study that investigated mindfulness-based interventions in psychiatric disorders.21 Dr Greven suggested that mindfulness could be useful in ADHD, as in her experience it targets self-control, attention, emotional regulation and depression. She then highlighted a meta-analysis study that showed that mindfulness may have possible benefits in reducing symptoms of ADHD.22 Dr Greven then provided some suggestions for future mindfulness studies in patients with ADHD including: randomised controlled trials with large sample sizes; inclusion of medically naïve patients; measurements of a wider range of symptoms and not just core ADHD symptoms; and a focus on long-term studies. Dr Greven then discussed the ongoing randomised controlled trial she is conducting, called ‘MindChamp’, which is investigating the effects of family-based mindfulness as an add-on to care-as-usual in children with ADHD; the protocol for this trial has recently been published.23
Professor Philip Asherson (King’s College London and Maudsley Hospital, London, UK) started the next session by discussing mind wandering, and indicated that there is evidence to suggest that spontaneous mind wandering is a central feature of ADHD symptomatology.24 He explained that, in his opinion, excessive mind wandering could lead those with ADHD to become more distracted from current tasks by internal thoughts and may also cause problems in strategic thinking, as well as disrupted sleep. Professor Asherson’s PhD student, Natali Bozhilova (Department of Social Genetic & Developmental Psychiatry, King’s College London, London, UK) then discussed a theoretical model of the brain mechanisms of mind wandering and how this relates to impairments of ADHD.25 She indicated that they are currently investigating mind wandering in ADHD.
The questions and discussion from the audience highlighted that they thought the interaction between mindfulness and ADHD treatment is interesting but requires more research. The presenters also wanted to make clear that mindfulness is not the same as meditation.
Dr Greven: “Mindfulness appears to reduce symptoms in children and adults with ADHD … greater methodological rigour is needed for definitive conclusions.”
Professor Asherson: “Can we target mind wandering with mindfulness?”
Professor Phillip Asherson
ADHD and aggression
To open this session, Professor Jan Buitelaar (Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands) examined the taxonomy and neural underpinnings of ADHD and aggression. He went on to note that aggression is a symptom, not a diagnosis, and that aggression itself can be very heterogeneous.
Professor Buitelaar laid out an overview of his experience in subtyping of aggression, including impulsive versus instrumental aggression, early- versus late-onset aggression, socialised versus non-socialised aggression, and three psychopathic traits: callous-unemotional, impulsivity and narcissism. He also noted that aggression could be reactive (hot anger with high emotion and arousal, e.g. borne of frustration) or proactive (cold anger, with low emotion and arousal, e.g. a pre-planned act).
Professor Buitelaar went on to highlight the results from a study in 162 children and adolescents with oppositional disorder/conduct disorder and 92 control subjects, which looked at the structural profiling of specific brain areas and its association with subtypes of aggression. He noted that decreased amygdala and ventral striatal volumes were not specific for reactive and/or proactive subtypes of aggression, but callous-unemotional traits were associated with amygdala volume.26 He also presented data from a study looking at the neurochemical profile in aggression in ADHD, but these data have not yet been published.
Following the opening presentation, Dr Jeffrey Glennon (Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands) looked at the topic of inattention potentially being causal to aggression. He provided an overview of murine models of inattention and aggression, as well as looking at data from humans. He presented results from studies that examined aggression in aggressive BALB/cJ and non-aggressive BALB/cByJ mice, and human data from the NeuroIMAGE, ADHD-200 and IMpACT studies.
Dr Glennon concluded by highlighting that, in his opinion, we should focus on using both pharmacological and non-pharmacological strategies that target attention deficits in order to have knock-on effects on impulsivity, hyperactivity and aggression.
In the final presentation looking at ADHD and aggression, Professor Asherson presented his experience with treating prisoners with ADHD. He presented his experience from his role as chief investigator in the CIAO Project (Concerta XL In Adult Offenders).27 The project aimed to evaluate the effectiveness of long-acting MPH in reducing levels of aggression, increasing engagement with educational activities and reducing ADHD symptoms in 100 young male offenders with ADHD over a 12-week period. The study screened 1922 prisoners, of whom 306 met diagnostic criteria for ADHD following all assessments.27
Professor Asherson noted that, in his opinion, emotional lability is a very common factor in prisoners and this, along with the desire to be able to concentrate (typically to gain further education), was said by prisoners to be one of their key motivations to be treated for ADHD.
The study reported a small-to-moderate reduction in the number of adjudications from baseline to the end of the study, and found substantial changes in symptom levels. Interestingly, the majority of patients had a preference for a lower dose of treatment, possibly due to increased sensitivity to adverse events but also minimal diversion of the drug.27
Professor Asherson concluded with feedback directly from the Prison Inspectorate, stating that “All prisoners were offered screening for attention deficit hyperactivity disorder (ADHD) through the specialist Concerta (an ADHD treatment) in adult offenders (CIAO) trial … Some prisoners on the CIAO programme to whom we spoke were experiencing some stability of behaviour for the first time in their lives”.
Professor Asherson: “A prisoner once said that “Following treatment, now when I’m provoked into aggression I am able to stop, think, and make another choice”.”
Dr Iris Manor
The placebo response
This session began with Dr Iris Manor (ADHD Clinic, Geha Mental Health Center, Petah-Tikva, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel) explaining the rationale for the use of placebo. She then clarified that the placebo response is “the sum of all non-specific aspects of response which are not due to active medication”. Dr Manor stated that, in her experience, the placebo response interacts with drug treatment and varies depending on a variety of factors such as patient age, patient expectancy of treatment outcome, the randomisation ratio, and whether the treatment is given as a monotherapy or as a combined treatment. Dr Manor also said that, in her opinion, the relative timing of treatment and the study duration can affect the placebo response.
Dr Manor then highlighted that there are limited data available that compare the magnitude and nature of the placebo response in different primary measures of ADHD, and introduced a retrospective cohort analysis which she conducted to characterise the placebo response in adults with ADHD.28 Results from this study showed that the placebo response was prominent on symptom scales for ADHD as well as investigator-rated scales.28 Dr Manor emphasised that these data suggest that using investigator-rated scales as a primary endpoint does not mitigate the placebo response, and interestingly, clinical trials should use more self-reported measures.28 Dr Manor concluded that further studies are required to identify the mechanisms involved in the placebo response in ADHD and that clinical trials should attempt to minimise the placebo response so as to gain an accurate assessment of a medication’s efficacy.
Professor Newcorn then presented an overview of the placebo response in published ADHD clinical trials, and highlighted a study which had used changes to the study design to mitigate the placebo response.29 He highlighted that, in his opinion, minimising the placebo response may be particularly important when investigating new drugs which have low-to-medium effect sizes.
The discussion was then opened to the audience, and one audience member asked for the presenters’ thoughts on the ‘nocebo effect’, which, it was agreed, was different to the placebo response. Another member of the audience queried whether the placebo response has any real effects in patients with ADHD. Using their clinical experience, Professor Newcorn and Dr Manor indicated that following treatment, patients with ADHD often understand how they should respond to questions on ADHD rating scales and how they should behave following treatment, which could complicate the placebo response.
Dr Manor: “[The placebo response] has particular relevance to disorders regulated by dopamine neurotransmission, such as Parkinson’s and ADHD.”
Professor Newcorn: “The type of study matters … how long your study is … and what you tell [your patients] about the drug … the placebo response describes everything that happens in your trial that is not due to the active drug.”
Dr Julia Rucklidge
Medical and nutritional interventions
Opening the final symposium, chaired by Professor David Coghill (Department of Paediatrics and Psychiatry, University of Melbourne, Melbourne, Australia), Dr Samuele Cortese (University of Southampton, Southampton, UK) provided a summary of a large systematic review and network meta-analysis investigating the comparative efficacy and tolerability of medications for ADHD in children, adolescents, and adults.30 The primary outcomes were efficacy (change in severity of ADHD core symptoms based on teachers’ and clinicians’ ratings) and tolerability (proportion of patients who dropped out of studies because of side effects) over 12, 26 and 52 weeks.
The investigation covered data obtained from multiple sources, with the analysis of efficacy at 12 weeks based on 10,068 children and adolescents and 8131 adults, and the analysis of tolerability based on 11,018 children and adolescents and 5362 adults; and included 133 double-blind randomised controlled trials (81 in children and adolescents, 51 in adults, and one in both).30 Looking at the primary endpoint (efficacy on core symptoms), the study found that all drugs with available data were shown to be more effective than placebo (except for modafinil in adults) when rated by clinicians. With respect to tolerability, the results favoured placebo in several cases (amfetamine [in both age groups]; atomoxetine, MPH and modafinil [in adults only]; and guanfacine [in children and adolescents only]). The network meta-analysis then went on to provide an in-depth look at indirect drug–drug comparisons for each of the primary and secondary endpoints.30
Dr Cortese made it very clear that this paper was not meant to be taken as a guideline, nor any form of official recommendation, but as a piece of advice based on robust statistical analysis at a group level. He also highlighted the need for more long-term randomised clinical trials to be conducted. He concluded by stating that when both efficacy and safety is taken into account, the evidence gathered and analysed in the study supports the use of MPH in children and adolescents and amfetamines in adults as preferred first-choice medications for the short-term treatment of ADHD.30
In the second presentation of the symposium, Professor Banaschewski presented the study design and preliminary unpublished results from the Attention Deficit Hyperactivity Disorder Drugs Use Chronic Effects (ADDUCE) study.
He explained that the primary component of ADDUCE is a 2-year longitudinal, naturalistic, pharmacovigilance study being conducted at 27 European sites, which has recruited three cohorts of children and adolescents (aged 6–17 years) living in the UK, Germany, Hungary and Italy:31
- Group 1 (medicated ADHD): a total of 800 ADHD medication-naïve children and adolescents diagnosed with ADHD about to start MPH treatment.
- Group 2 (unmedicated ADHD): including 400 children and adolescents with ADHD who have never been treated with ADHD medication and do not intend to take medication.
- Group 3 (non-ADHD): made up of 400 children and adolescents without ADHD who are siblings of individuals in either Groups 1 or 2.
The primary objectives of the ADDUCE study31 are the potential long-term effects of MPH use on growth and height. Secondary objectives examined cardiovascular outcomes, and psychiatric symptoms and neurological outcomes. Professor Banaschewski concluded by saying that it is hoped that the final results from this study will be published within the next year.
The final presentation of the day, by Dr Julia Rucklidge (University of Canterbury, Christchurch, New Zealand), provided a brief overview of nutrition as a treatment in ADHD. She provided an overview of epidemiological studies looking at associations of dietary patterns to ADHD, both in patients themselves and the impact of maternal nutrition. Following this, she took the audience on a journey through all of the food items and additives that have been areas of focus or thought to be related to ADHD throughout the decades, including food dyes and colourings, and other additives.32 She also provided a look at restricted elimination diets, which may show that although diet is probably not the cause of ADHD, it may have an additive effect.33 She also noted that, in her opinion, these types of diets can be difficult to implement as there are no diagnostic tests and no two children’s needs are the same, and they can also be socially isolating, disruptive and expensive.
Dr Rucklidge highlighted that, in her experience, some effect may be observed with use of omegas in patients with ADHD, but the mechanism of action is yet to be confirmed.
She felt that it is important that every clinician should talk to their patients about their diet. In her opinion, they should be encouraged to eat a whole-food diet, with “real” foods as opposed to processed foods, while limiting sugar intake – generally encouraging a healthy diet.
Dr Rucklidge summarised her presentation by highlighting that, in her opinion, there are two sides to the nutrition coin. There are items that we do eat that maybe we shouldn’t eat (e.g. allergens, casein, dairy, gluten, artificial additives and colours) and there are items that we are not eating enough of (e.g. vitamins, minerals, and omega-3 fatty acids).
Dr Rucklidge: “While making food colour exclusions might not make much of a difference for most people, in those that it does make a difference, it would be life changing.”
Disclaimer: The views expressed here are the views of the presenting physician and not those Takeda
- Chang Z, Quinn PD, Hur K, et al. Association between medication use for attention-deficit/hyperactivity disorder and risk for motor vehicle crashes. JAMA Psychiatry 2017; 6: 597-603.
- Lichtenstein P, Halldner L, Zetterqvist J, et al. Medication for attention deficit-hyperactivity disorder and criminality. N Engl J Med 2012; 367: 2006-2014.
- Chen Q, Sjölander A, Runeson B, et al. Drug treatment for attention-deficit/hyperactivity disorder and suicidal behaviour: register based study. BMJ 2014; 348: g3769.
- Chang Z, Lichtenstein P, Halldner L, et al. Stimulant ADHD medication and risk for substance abuse. J Child Psychol Psychiatry 2014; 55: 878-885.
- Chang Z, D’Onofrio BM, Quinn PD, et al. Medication for attention deficit/hyperactivity disorder and risk for depression: a nationwide longitudinal cohort study. Biol Psychiatry 2016; 80: 916-922.
- Raman SR, Man KKC, Bahmanyar S, et al. Trends in attention-deficit hyperactivity disorder medication use: a retrospective observational study using population-based databases. Lancet Psychiatry 2018; Epub ahead of print.
- Man KKC, Ip P, Chan EW, et al. Effectiveness of pharmacological treatment for attention-deficit/hyperactivity disorder on physical injuries: a systematic review and meta-analysis of observational studies. CNS Drugs 2017; 31: 1043-1055.
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