Clinical Hot Topic 5: Headlines from recent publications in ADHD

Moderator: Professor Joseph Sergeant (Emeritus Professor of Clinical Neuropsychology, Vrije University, Amsterdam, The Netherlands)

Professor Joseph Sergeant opened the session by introducing the two speakers, Professor Luis Rhode (Professor of Child & Adolescent Psychiatry, Federal University of Rio Grande do Sul, Porto Alegre, Brazil) and Professor Tobias Banaschewski (Professor of Child & Adolescent Psychiatry, Central Institute of Mental Health, Mannheim, Germany). Each speaker went on to present key findings from recent publications in order to bring the audience up to date on current research on ADHD published in 2019–2020.

The first study was presented by Professor Rohde, who discussed findings of a meta-analysis published in 2020 that assessed evidence pertaining to emotional dysregulation in adults with ADHD.1 The key finding of the meta-analysis was that adults with ADHD have more emotional dysregulation compared with adults without ADHD. Emotional dysregulation was also a distinct feature of ADHD in adulthood.1 Furthermore, ADHD severity was found to be related to the level of emotional dysregulation expressed by an individual, for example, emotional lability, emotion recognition and emotional responses.1 Professor Rohde suggested that the next research question in this area is “How specific is the emotional dysregulation construct for ADHD?”

The second study was presented by Professor Banaschewski who discussed findings from a randomised controlled trial that investigated the use of a novel digital intervention in the form of a video game (Software Treatment for Actively Reducing Severity of ADHD [STARS-ADHD]) that targets attention and cognitive control in children with ADHD.2 The trial data showed that the treatment group had improved attentional control and ability to shift their attention between tasks compared with the control group.2 However, there was no difference between the groups in the secondary measures (between-group comparisons of pre-intervention and post-intervention change in rating scales scores). Additionally, there is currently limited evidence for the long-term and generalised population effects of this novel digital therapy.2 Professor Banaschewski concluded his discussion of this study by suggesting that the therapy may not replace current standard of care, but it may be beneficial to children with ADHD who currently do not have access to non-pharmacological interventions.

Professor Rohde went on to present the third study, which was a meta-analysis that investigated the efficacy of non-pharmacological treatments on comorbid internalising symptoms of adults with ADHD.3 The authors’ key take-away conclusion from this study was that cognitive behavioural therapy improved comorbid internalising symptoms in adults with ADHD.3 However, Professor Rohde stated that the data and conclusions should be interpreted with caution, as only a small number of trials evaluated some of the therapies that were analysed.3 Additionally, there was a high risk of bias observed in the studies, which may further limit the results of the meta-analysis.3

The fourth study evaluated the development of a novel risk calculator to predict adult ADHD, and was presented by Professor Banaschewski.4 Based on childhood characteristics, the risk calculator was able to predict adult ADHD in European and North American population-based cohorts and clinical samples with comparable discrimination to that of other clinical tools.4 However, Professor Banaschewski stated that the risk calculator does not demonstrate accuracy in middle-income settings and therefore needs further investigation to determine the reasons behind this. Further trials to examine these differences in results are also needed.4 Furthermore, he stated that the calculation for the risk calculator is misleading, as it gives equal weight to all measures of ADHD.

The fifth study, presented by Professor Rohde, reviewed the pharmacological treatment of ADHD between 2001 and 2015.5 A key finding of the review was that the prevalence of medication use worldwide was much lower than the number of people with ADHD, except in the United States and Iceland.5 Additional findings noted that the average length of treatment duration with stimulants was 136 days in children and 230 days in adults during the first year of treatment.5 Professor Rohde indicated that this highlights that adherence to treatment is a continuous clinical challenge in ADHD. The final key finding of the review was that clinicians use a trial-and-error method to determine the most appropriate medication for individuals with ADHD, as the current understanding of the neurobiology of ADHD is not sufficient to inform clinical opinion.5 Professor Rohde reiterated that, for this reason, clinicians need to develop the skills required to sufficiently manage individuals with ADHD. Professor Rohde felt that better biological markers are required to aid clinicians and inform opinion on the appropriate medication for those with ADHD.

The sixth and final study, presented by Professor Banaschewski, discussed mortality and methylphenidate (MPH) in children with ADHD.6 The results showed that there was a decrease in all-cause mortality when children with ADHD were treated with MPH (adjusted hazard ratio 0.81 [95% confidence interval (CI) 0.67‒0.98]; p=0.027).6 Additionally, there was a reduction in mortality when children with ADHD received long-term MPH therapy (adjusted hazard ratio 0.83 [95% CI 0.70‒0.98]).6 Conversely, delayed prescription of MPH was associated with an increase in mortality (adjusted hazard ratio 1.05 [95% CI 1.01‒1.09]).6 Professor Banaschewski stated that this highlighted the importance of when to treat individuals with ADHD and for how long they are treated.

Professor Sergeant concluded the session by emphasising that this research is a work in progress that requires more investigation. He also noted that the transfer of this research to clinical practice is increasingly important for helping to establish the relevance of these studies.

Professor Rohde: “Developing strategies to [increase] adherence to treatment is yet a clinical challenge”

Professor Banaschewski: “To treat ADHD is easy, but to treat it well is difficult”

Professor Sergeant: “The transfer of basic research into clinical practice is becoming more and more important to establish the relevance of what we’re doing”

Clinical Hot Topic 6: Psychological interventions, across the lifespan, for ADHD

Dr Susan Young (Consultant Forensic and Clinical Psychologist, Private Practice, London, UK) opened this session by discussing non-pharmacological interventions for ADHD. Non-pharmacological therapies for ADHD may involve behavioural, psychological, social, educational and lifestyle interventions.7-13 Dr Young stated that, in her opinion, the most commonly used non-pharmacological therapy for ADHD is likely to be psychoeducation. She noted that this intervention teaches individuals with ADHD, their families and teachers about ADHD, and is delivered either indirectly, via written content, or directly by the clinician at a consultation or during group education sessions. Dr Young indicated that she feels psychological therapies are active treatments that provide techniques for change, coping strategies and skills to enable changes in quality of life. For children with ADHD, Dr Young indicated that these are usually behavioural interventions, which can be parent-led, whereas adolescents with ADHD may receive more direct therapy such as cognitive interventions. Other non-pharmacological therapies for ADHD may include increasing physical activity and dietary changes; however, Dr Young stated that there is currently limited evidence for the effectiveness of these interventions.

Dr Young next explained that when using a lifespan approach to non-pharmacological treatment of ADHD, the mode of delivery changes as the individual’s ability to absorb and implement psychological techniques advances. Non-pharmacological therapies may begin as parent-led training and become more directive as the individual with ADHD reaches adulthood.14 Dr Young reminded the audience that children with ADHD will go through key life milestones as they transition into adulthood, such as attending secondary school, university and work. She noted that such changes may unsettle individuals with ADHD, who may require modification of psychological treatments during these key developmental phases. Dr Young emphasised that it is important to remain aware of an individual’s understanding of their own behaviour and treatment.14,15

Dr Young next highlighted some of the clinical guidelines for ADHD. For example, according to the National Institute of Health and Care Excellence (NICE), an ADHD-focused group parent-training programme should be offered to parents and carers of children aged <5 years with ADHD as a first-line treatment. For those aged ≥5 years, medication can be offered only if ADHD symptoms still cause significant impairment after environmental modifications have been implemented and reviewed. Prior to medication initiation, the individual with ADHD and their parents or carers must have discussed information about ADHD, and a baseline assessment must have been conducted. For adults with ADHD, medication is recommended if symptoms are still causing a significant impairment following the implementation of environmental modifications. Adults with ADHD should be also be offered, as a minimum, non-pharmacological treatment in the form of a structured supportive psychological intervention focused on ADHD and a regular follow-up either in person or by phone.7 Dr Young stated that, in her opinion, sometimes the support of non-pharmacological interventions is lost when medication is introduced. She noted that it can be disappointing when non-pharmacological therapies fail to alleviate all ADHD symptoms and the individual does not have the skills to cope with their disorder. In her experience, an individual with ADHD is usually first assessed when a critical incident occurs and the individual’s response to the incident impacts their symptoms. Dr Young then went on to explain the different levels of psychological therapy using her clinical knowledge. She stated that counselling or coaching may offer advice to the individual with ADHD. Cognitive behavioural therapy (CBT) – or behaviour therapy/dialectical behaviour therapy/cognitive analytic therapy – also works on the presenting problems by helping the individual to separate their thoughts, feelings and behaviours to understand their symptoms better.

Next, Dr Young introduced the Young–Smith programme, a CBT intervention for children aged 5‒12 years with ADHD, which focuses on the relationship between cognition, affect, body response and behaviour.16 The programme can be delivered by healthcare professionals, parents/carers, teachers and those involved in other agencies that support children with ADHD, due to its high level of structure. Dr Young listed the programme content, which included age-appropriate methods for working with young children through the introduction of a boy called ‘Buzz’ and his family. Each module contains worksheets that describe the adventures and difficulties encountered by Buzz in his everyday life. These worksheets include a stimulus sheet (which tells a story about Buzz and a related problem), a discussion sheet (which prompts the therapist to pose questions to the child) and a task sheet (where the child completes exercises to help Buzz solve the problem). Dr Young presented an example worksheet to show how this programme aims to build a relationship between the therapist and the child, to promote the child’s ability to express themselves. Through the discussion worksheet, the therapist encourages the child to reflect upon their own life, which Dr Young pointed out is useful because children with ADHD may be reluctant to talk about their own lives and problems.16

The next part of Dr Young’s presentation described a CBT programme for working with adolescents and adults with ADHD, named the Young–Bramham programme.17 She explained the psychological treatment paradigm basis behind the programme: the neuropsychological deficit, in this case ADHD, sits at the top of the model, below which are life events and experiences that are affected by ADHD. Dr Young highlighted that when a situation or task is presented, there are two outcomes: success or failure. The outcome of a situation or task depends upon the symptoms and experiences of the person, e.g. symptoms of impulsivity and inattention in ADHD may lead to outcome failure. Building on this concept, Dr Young highlighted that appraisal of successes or failures is key to future success. She noted that success leads to positive appraisal, which reinforces positive thoughts, feelings and behaviour, whereas failure can lead to negative appraisals and negative thoughts, feelings and behaviour. Dr Young stated that as a therapist, her aim is to encourage those with ADHD to reappraise their failures so that they can achieve positive appraisal and resilience.

In further detail, Dr Young described how this programme uses more direct and complex techniques targeted at adults. These techniques include cognitive remediation strategies, cognitive reframing of the past, restructuring and reasoning, rationalisation, compensatory strategy development and behavioural techniques. This CBT programme comprises a background and treatment section of ADHD, ‘core symptom’ modules, ‘comorbid and associated problem’ modules and ‘the future’ module. Dr Young emphasised the importance of ‘the future’ module for preparing individuals with ADHD for the future. Dr Young then presented an example of the ‘organisation and time-management problem’ submodule. In this submodule, the individual with ADHD has to identify and define the problem specifically and then apply a stepped time plan in which goals are set in achievable steps. She indicated that throughout this submodule, tasks are scheduled and planned breaks and rewards are incorporated. The coaching techniques used in the Young–Bramham CBT programme include positive thinking and mentoring, breathing, relaxation and behavioural experiments.17

Dr Young then described the three-legged table analogy of CBT, in which the problem sits on top of maladaptive thoughts, feelings and behaviour patterns. To approach the problem, one of these three legs must be broken, i.e. the thought, feeling or behaviour must be changed. For example, Dr Young indicated that challenging negative thoughts or changing body posture may be an intervention to the problem. Dr Young also presented a working example of interpersonal relationship problems and how the Young–Bramham programme teaches individuals with ADHD to identify and define the problem. In doing so, a clearer picture of the problem can be obtained before treatment strategies are delivered, such as rehearsing conversational ‘rules’, role-play and constructive self-talk. Then Dr Young explained how towards the end of the Young–Bramham programme, more fundamental beliefs are addressed via scheme-focused therapy so that the individual with ADHD can understand what initially led to their problems.

In the final part of her session, Dr Young introduced her new concept of psychological mind mapping. Using these mind-mapping techniques, the development of the mind is uncovered, from the pre-wiring of neurological deficits to the symptoms of ADHD and the maladaptive thoughts, feelings and behaviour patterns associated with the three-legged table of CBT. Dr Young then explained that the aims of this paradigm are for individuals with ADHD to:

  • Understand and accept the past
  • Understand and reflect on their developmental pathway
  • Identify the schema(s) (the pattern[s] of thought and behaviours that, in the case of ADHD, are deemed to be maladaptive – e.g. “I’m defective” leading to “I’m dependent”) and look for cumulative effects
  • Weaken the schema
  • Move between a subconscious to conscious process
  • Revisit life events and map schema development and escalation
  • Look for ‘switches’ – a change or break away from a schema
  • Cognitively reframe events that led to the schema
  • Have a new insight that impacts on future appraisal, perspective, response to challenges and problems.

Dr Young concluded that although this mind-mapping approach was originally used for personality disorders, she believes it could be helpful to individuals with ADHD.

Dr Young: “Psychological therapies are generally more active treatments, providing strategies and techniques for change”

Psychopharmacology of ADHD medications

Moderator: Dr Duncan Manders (Consultant Child & Adolescent and Intellectual Disabilities Psychiatrist, Royal Hospital for Sick Children, NHS Lothian, Edinburgh, UK)

Professor David Coghill (Financial Markets Foundation Chair of Developmental Mental Health, Royal Children’s Hospital, Melbourne, Australia) began his presentation by providing a short summary of the various cerebral pathways that are involved in ADHD. The pathways discussed were the executive function and corticocerebellar (motor control) systems, the reward network, and the dopaminergic and noradrenergic systems. The dopaminergic and noradrenergic systems were the main focus of this session, because medications for ADHD can affect this system. Professor Coghill stated that, during normal brain functioning, the levels of noradrenaline (signal control) and dopamine (noise control) are balanced.18 However, in people with ADHD, levels are reduced, which leads to inattention, fidgeting, and reduced ability to focus and stay still.18

Professor Coghill provided a further summary of the hypothesised effects of ADHD medication on the prefrontal cortex. MPH blocks the dopamine transporter on dopaminergic neurones in order to prevent reuptake of dopamine back into dopaminergic systems and improve noise control.19 Additionally, MPH blocks the noradrenaline transporter to prevent noradrenaline reuptake and improve signal control within the prefrontal cortex.19 Professor Coghill stated that amfetamine works in much the same way as MPH. However, amfetamine has an additional action whereby it can be taken up by the dopaminergic transporter into the presynaptic neurone alongside dopamine, such that cathecholamines are released into the synaptic cleft. Additionally, due to MPH and amfetamine having different structures, individuals with ADHD may exhibit variable effects to treatment. Another pharmacological therapy for ADHD, discussed by Professor Coghill, was atomoxetine (ATX), which specifically binds to noradrenaline transporters and thus has no effect on dopaminergic neurones.19 However, Professor Coghill stated that as the majority of dopamine transport occurs through noradrenaline transporters, ATX has the ability to affect the actions of dopamine within the prefrontal cortex. The final pharmacological therapy that Professor Coghill summarised was guanfacine, which directly mimics noradrenaline beneficial actions at postsynaptic α-2A adrenoreceptors in the prefrontal cortex.19,20

The importance of pharmacokinetics in relation to stimulant actions

MPH

Professor Coghill moved on to discuss the bioavailability of different MPH formulations. He presented adapted data that highlighted the differences in plasma levels of various immediate- and extended-release formulations of MPH throughout a 15-hour period (a working day). A dose of 20 mg immediate-release MPH leads to peak plasma levels occurring early in the day, such that a second dose is required later in the day in order to maintain effects throughout this period of time.21,22 An MPH dose of 54 mg that is a mixture of 22% immediate-release MPH (contained in the tablet overcoat) and 78% extended-release MPH (released from the tri-layer core by an osmotic process) leads to a peak in plasma levels occurring later in the day, but with a lower peak than another formulation – three capsules of 20 mg MPH (30% immediate-release MPH and 70% extended-release).23 Finally, data of 40 mg dose of long-acting MPH showed a fast increase to peak plasma levels, which then remained steady over a few hours.22,24 Overall, Professor Coghill explained that clinicians need to be aware of the pharmacokinetic properties of the various formulations of MPH in order to provide optimal treatment responses in individuals with ADHD, due to the different response times of the formulations.

Amfetamines

Professor Coghill used the prodrug lisdexamfetamine (LDX) as an example of the pharmacokinetic properties of amfetamines.25,26 He explained that LDX is inert and is only active once it is broken down into lysine and d-amfetamine.25,26 Therefore, plasma levels of LDX peak early before being broken down in the hepatic system into lysine and d-amfetamine.25,26 Professor Coghill suggested that the effects of d-amfetamine occur over an extended period due to the time it takes for the hepatic system to break down LDX. The effects of d-amfetamine are proportional to the initial dose of LDX taken by the individual. In other words, the larger the dose of LDX, the longer it takes for LDX to be broken down, so the higher the plasma concentration of d-amfetamine, and therefore, the longer the drug is bioavailable before being broken down by the hepatic system.

ATX

Professor Coghill explained that ATX, similar to LDX, is a slow-release pharmacological therapy for ADHD. In one study, data highlighted that optimal effects of ATX occur around 12 weeks post-initiation of treatment (effect size increased 0.55–0.82 between Weeks 6–12).27 Professor Coghill expressed that, in his opinion, this does not mean that treatment effects would begin to fall 12 weeks following ATX initiation, but would in theory keep improving.

Guanfacine

Professor Coghill did not present study data pertaining to the pharmacokinetics of guanfacine; however, he stated that the positive effects of guanfacine take around 4–6 weeks to develop. Additionally, Professor Coghill stipulated that, in his clinical practice, he typically administers guanfacine for a trial period of 6 weeks to determine treatment effect.

Professor Coghill concluded with the following take-home messages, based on his clinical experience:

  • Clinicians should learn the pharmacokinetics of stimulants for ADHD and understand the balance between extended-release and immediate-release formulations.
  • When switching individuals with ADHD from immediate- to extended-release formulations, clinicians should titrate the morning dose to the previous immediate-release dose in order to make the transition between medications easier.

Professor Coghill: “People find pharmacokinetics a dry and boring subject … to get the maximum out of a stimulant, it’s imperative you understand”

Ask the Experts: Sessions 1, 2 & 3 (discussion forum)

Moderator: Dr Duncan Manders (Consultant Child & Adolescent and Intellectual Disabilities Psychiatrist, Royal Hospital for Sick Children, NHS Lothian, Edinburgh, UK)

Panel: Professor David Coghill (Financial Markets Foundation Chair of Developmental Mental Health, Royal Children’s Hospital, Melbourne, Australia); Professor David Nutt (Edmond J. Safra Professor of Neuropsychopharmacology/Director of the Neuropsychopharmacology Unit in the Division of Brain Sciences, Imperial College London, London, UK); Professor Stephen Faraone (The State University of New York Upstate Medical University, Syracuse, NY, USA)

For this session, Dr Manders presented the panel with questions put forward by the audience, and members of the panel provided answers based on their own clinical expertise and experience. Below is a summary of their responses.

‘Can you please comment on emotional regulation in ADHD and the consideration of it as a core symptom in any future revision of the diagnosis?’

Professor Coghill stated that although he believes the emotional dysregulation observed in ADHD is a core symptom, he does not suggest including it in future revisions of the diagnosis, because it is unhelpful as a criterion to distinguish ADHD from other disorders, which is the purpose of a criterion for diagnosis in his opinion. For example, irritability is seen in ADHD but also in many other disorders, and has a stronger affiliation to emotional disorders than neurodevelopmental disorders.

Professor Nutt explained that emotional dysregulation is the failure of prefrontal cortical organisation and top-down control of emotions. He suggested that patients may need selective serotonin-reuptake inhibitors to deal with emotional problems such as anxiety, and that to him, this coexistence of ADHD and emotional problems is the norm.

From a child and adolescent perspective, are there any particular drugs that better aid in the management of the emotional component of ADHD?’

Professor Coghill explained that he has found that when treatment for ADHD symptoms is optimised, usually starting with stimulants, then a significant reduction in emotional instability is often observed. He went on to describe particular drugs that have shown effectiveness, in his experience.

‘Professor Faraone, for anyone who missed your presentation, could you briefly describe what you mean by subthreshold ADHD?’

Professor Faraone explained that subthreshold ADHD is where ADHD symptoms are experienced but the threshold for diagnosis is not met. Despite this, a patient may seem to the clinician to have ADHD and may have a family history of ADHD.

‘Could you explain how environmental factors translate at a neurobiological level in ADHD, particularly in relation to attachment disorder, deprivation and neglect?’

Professor Nutt explained that deprivation, neglect and negative psychological inputs can have effects on brain size, decreasing the size of most areas except the amygdala (associated with fear and stress), which may become larger.

‘What are the implications for assessment and treatment of the overlap with those conditions?’

Professor Coghill added that the implications of this overlap suggest that it is more likely people with ADHD have experienced abuse. He then noted that ADHD isn’t usually caused by stress or trauma, but the risk of developing it increases with these factors, so that there is an additive effect.

‘ADHD has such a strong genetic heritability; how do you account for it accounting for only 5–8% of the population?’

Professor Faraone stated that the strength of genetic causality of the disease has nothing to do with the prevalence of ADHD. The prevalence has to do with how common the alleles are in the population. He used the example of Huntington’s disease being 100% heritable, but also relatively rare in the population due to it being caused by a rare gene.

‘Have the norms of sustaining attention shifted since infants started watching YouTube videos?’

Professor Faraone stated that he does not know of data to support the question, but that there is no evidence to suggest that infants watching YouTube is causing the development of ADHD. He expanded on this by saying that there has always been a question of whether the stresses of modern-day society or changes in technology habits (e.g. video games) have caused an increased prevalence of ADHD. He then referred to a meta-analysis of ADHD prevalence estimates across three decades, which found no evidence to suggest there has been an increase over time in the number of children who meet criteria for ADHD.28

‘How/should we change the conversation from a symptom rating scale to an impairment scale?’

Professor Faraone suggested that the answer is that we have to do both in order to figure out the best treatment. He added that we need to help diagnose impairment in better, novel ways.

Professor Coghill agreed and explained that when treating patients in the clinic, he focuses on the symptoms first as these can be effectively controlled with medication. Then he looks to his patients’ broader functioning, as usually some deficits (such as cognitive and educational) may not be treated with medication.

Professor Nutt added that it is important to monitor treatment, as treating ADHD may uncover comorbid disorders that the person has.

‘Are there any changes to the neurotransmitter systems throughout childhood and from preschool to adolescence that can be accelerated with the early initiation of medications?

Professor Nutt stated that he believes there are no data to support early initiation of medications. However, there is a huge amount of data to support the ability of treatment to reduce impairment and school refusal. Furthermore, there are also no data to suggest that medication impairs development.

Professor Coghill added that education and the social interaction that comes with going to school have a positive impact on children with ADHD. Therefore, if giving a child medication will help them to stay in school, then it is having a positive impact.

Professor Faraone built on this by describing functional magnetic resonance imaging studies that have shown that atypical changes in the brains of people with ADHD are not due to taking medication. Furthermore, he added that longitudinal studies to monitor brain changes from taking medication for ADHD have suggested that individuals’ brains became more neurotypical over time with medication. However, he added that this was indirect evidence and must be interpreted with caution.

‘How can we follow-up the medical effect of ADHD, since the effect is quite subjective to patients? How do you monitor treatment?’

Professor Coghill emphasised that measurement-based care is the best way forward. He explained that this meant routinely measuring outcomes and changing treatment based on any outcome changes. He explained that a holistic approach should be taken to observe all areas of functioning and not just symptoms.

Professor Faraone added that these outcome measures should be reproducible objective measures. He explained that there is a tendency to think that asking questions is a subjective measure, but it can be done objectively if questions are asked in the right way.

‘Why do some people on stimulant medicines have low mood as a side effect with respect to the effects on the neurotransmitters?’

Professor Nutt explained that it could be partly that the person had low mood before the stimulant medication, but that their ADHD was obscuring it as the symptoms of ADHD were bigger presenting problems. He added that it is possible there is an enduring effect of stimulants on the serotonergic system, but that he is unsure what the answer to this question would be.

‘How do you decide which medicine to use first and why?’

Professor Coghill replied that in almost all cases you use a stimulant first. However, there is no way to tell who will respond better to which stimulants, so deciding which stimulant to use first is difficult. Nevertheless, he added that if the patient does not respond well to the first stimulant, it means there is a high chance that they will respond better with the next one tried.

‘Can the panel comment on treatment continuation versus treatment holidays?’

Professor Nutt explained that this is a question that is asked a lot, generally in the context of growing suspicion that chronic stimulants might damage the brain. However, he stated that a treatment holiday has to serve a purpose other than to alleviate this anxiety. Patients may want a break from a certain side effect, or they may have gained a degree of tolerance to it. He suggested that patients should take this break at a time when they have few outside pressures, so that they are able to cope without the medication.

Professor Faraone added that clinicians thinking of treatment holidays for their patients should remain aware that this puts the patient at risk of a number of negative functional outcomes, such as increased criminality or suicidality.

Dr Manders concluded the ‘Ask the Experts’ panel by asking each panellist for a final take-home message, from either their presentation or this discussion.

Professor Faraone summarised how undertreatment of ADHD is a huge mistake; people may be understandably worried about negative effects of medication, but not worried enough over the impairments of the untreated individual with ADHD.

Professor Nutt: ‘Stimulants as used in ADHD are not addictive’

Professor Coghill: ‘Measure, measure, measure, measurement-based care, I think that needs to be a mantra for us all over the next 10 years and we really need to make it the norm within routine clinical care’

Clinical Hot Topic 7: A deeper dive into the (clinical) psychopharmacology of ADHD medications

Professor David Coghill (Financial Markets Foundation Chair of Developmental Mental Health, Royal Children’s Hospital, Melbourne, Australia) started the session by discussing his method of providing the required medication dose for his patients with ADHD. In Professor Coghill’s own practice, he tries to titrate to the optimal dose of ADHD treatment to ensure maximum benefit at the minimum dose. This will often include titrating past the optimal dose initially, to be sure that the optimal dose has been achieved and that there were no added benefits of increasing the dose. If there are still impairing symptoms, then he would try a higher dose within the limits of the licence. He also highlighted the importance of asking the patient about continuing symptoms of ADHD rather than whether the medication is helping. He stated that the reason for this is due to variability in patient responses to stimulants, meaning that a clinician cannot predict how a patient with ADHD will respond. He went on to explain that around 70% of those with ADHD respond to one class of stimulant and 70% to the other, and 90–95% respond to either one or the other; therefore, if one doesn’t work, then try the next.29,30 Professor Coghill also noted that if a patient experiences adverse events when receiving one stimulant, it doesn’t necessarily mean that they will experience adverse events when receiving a different stimulant.29,30

Why do different people respond to different doses of stimulants?

Professor Coghill stated that it is not entirely clear why people respond differently to different doses of stimulant medication; however, he believes it is likely due to differences in drug metabolism rather than differences in either their absorption or how the drugs are acting at the brain level. Professor Coghill went on to present data that highlighted the differences in the metabolism of two formulations of methylphenidate (d-MPH and l-MPH).31-33 He explained that normally, the metabolism of MPH is a single-step process via carboxylesterase 1A (CES-1A), and under normal circumstances, the highest concentration of MPH observed after ingestion (the Cmax) is much higher for d-MPH than l-MPH.31,32 Professor Coghill noted that this is because stereoselective metabolism occurs on the first pass through the liver, where, under normal circumstances, almost all of the l-MPH is broken down and only the d-MPH is available in the peripheral circulation and therefore available for the brain.33 Evidence from a single study shows that variability in the CES-1A gene can have a substantial impact on the bioavailability of MPH.34 Professor Coghill went on to present results from a study by Zhu et al, which showed that the concentration of MPH (d– and l-MPH) in a patient who was a slow metaboliser (CES-1A mutation) was much higher than in the control subjects (n=19), and that the time to reach the maximum concentration (Tmax), the time to MPH metabolism and the half-life were also much slower in the slow metaboliser.31

Professor Coghill then explained the functional pharmacogenetics of carboxylesterases (CES), which are important drug-metabolising enzymes found predominantly in the endoplasmic reticulum of the liver, but also in other tissues lining the gut, the placenta and the brain.35 There are two main variants of the CES enzyme, CES1 and CES2; CES1 is the main enzyme responsible for the metabolism of MPH.35 Professor Coghill went on to revisit the study by Zhu et al, which showed that as well as differences in how MPH was broken down, there were also differences in the haemodynamic parameters in the patient with a CES-1A mutation.31 Results showed that pre-dose, there were no differences in haemodynamic parameters (systolic and diastolic blood pressure, mean arterial pressure and pulse); however, post-MPH, all of the haemodynamic parameters in the patient with a CES-1A mutation became abnormal.31 Professor Coghill suggested that this could indicate that some patients may be particularly sensitive to MPH, may experience increased adverse events, or could develop tolerance to MPH, and that further investigation is warranted.

Professor Coghill moved on to explain how lisdexamfetamine (LDX) is hydrolysed to d-amfetamine and l-lysine, and that most of the hydrolysis occurs in the red blood cells.25,26,36 He noted that when a patient takes LDX, there is a very quick initial peak in the plasma concentration of intact LDX after absorption, but then also a very quick breakdown of LDX that leads to a very sharp rise in plasma concentrations of d-amfetamine shortly after ingestion, which is the reason why LDX works relatively quickly.25 Unlike MPH, it is the LDX that is broken down in the first pass through the liver, rather than the d-amfetamine, which is relatively protected and hence is broken down much more slowly when it is in the peripheral circulation.36

Professor Coghill presented data that provided evidence of LDX being metabolised inside the cytosol of red blood cells.36 During the study, LDX was incubated with different blood components and then the concentration of LDX was measured over 4 hours.36 When LDX was incubated with peripheral blood mononucleated cells, polymorphonuclear cells or platelets, there was no decrease in LDX concentration.36 However, when LDX was incubated with red blood cells, there was a steady decrease in LDX concentration over the time period,36 therefore, providing evidence for the location of LDX metabolism into d-amfetamine and l-lysine.36 Professor Coghill stated that he believes this is what contributes to the extended duration of action of LDX, as d-amfetamine would have to leave the red blood cells via osmosis in order to cross the blood–brain barrier.

Professor Coghill highlighted study data which showed that the capacity of red blood cells to hydrolyse LDX is unaffected by red blood cell concentration or viability.37 Blood from two patients with sickle cell disease and two healthy controls was incubated with LDX, and the rate and magnitude of LDX hydrolysis was measured.37 The study showed that although there were some quantitative differences in how well and how fast the LDX was broken down, this difference was not significant between the patients and the controls, and the breakdown was very much adequate irrespective of the variation in red blood cell levels.37 Professor Coghill also noted that there is very little intra- and inter-subject variability in d-amfetamine pharmacokinetic parameters.38

Tolerance – does it exist and how can it be managed?

From his own clinical experience, Professor Coghill believes that tolerance must exist because people are able to accommodate adverse effects that are associated with ADHD stimulants, such as increased heart rate/blood pressure, decreased appetite and insomnia. There are also neurobiological findings in support of tolerance, such as upregulation of dopamine transporters with extended treatment.39 From his own clinical observations, Professor Coghill noted that it is not uncommon to require a gradual increase in dose over time, or for a higher absolute dose to be given to adolescents compared with children, which means that physicians need to appropriately adjust doses according to weight. He also noted ‘acute tolerance’, where higher blood levels are needed over the course of the day.40 However, Professor Coghill also explained that there are many patients who can be maintained on the same dose for long periods of time, and that medication holidays are not required in many individuals with ADHD receiving medication at a given dose.

Professor Coghill concluded his presentation by describing the differences between behavioural tolerance and pharmacological tolerance. Professor Coghill began by providing the audience with an example of “behavioural tolerance”:

A treatment-naïve individual with ADHD is first prescribed a stimulant and has not been titrated up to the maximum dose. However, the patient believes the drug is having a positive effect on their symptoms. This is because they have gone from no symptom control to some symptom control, but they have not reached optimal symptom control. After a few months, the patient realises that they are still experiencing quite a lot of symptoms and really the medication isn’t working so well – but the patient has become acclimatised to the effects and it is the new normal.

Professor Coghill emphasised that to avoid this scenario, standardised titration to reach optimal dose levels is necessary in order to get maximum benefit. However, even in those patients who receive optimum dose, patients can begin to experience symptoms again after a period of time and this is perhaps due to pharmacological tolerance. In order to eliminate pharmacological tolerance, Professor Coghill explained that he would typically allow for the medication to wash out of the individual’s system before restarting treatment to see whether this eliminates the tolerance. However, if symptoms do not improve after 1 week of wash out, then there may be other reasons why the medication is no longer working; for example, behavioural tolerance or an event/change in the patient’s life that is causing them to not be able to make use of their medication in the way that they previously were.

Professor Coghill: “Because response to medication is not predictable … it means we need enter treatment with an open mind”

Clinical Hot Topic 8: Utilising a range of pharmacological treatments in clinical practice: optimising treatment strategies

Dr Caroline Bleakley (Associate Specialist in Paediatric Neuro-disability, Ryegate Children’s Centre, Sheffield, UK) opened by describing the Ryegate Children’s Centre, which is a tertiary neurodisability service that helps over 1500 children aged up to 19 years with ADHD. She stated that in the time she has been working at the centre, there have been huge changes in the management and identification of ADHD. When she joined the team ~20 years ago, the centre would have largely just seen active boys. She expanded that back then, the Diagnostic and Statistical Manual of Mental Disorders–4th Edition was used to determine ADHD diagnoses, which did not take account of comorbidities such as autism spectrum disorder. In terms of medical treatment options, it was either immediate-release MPH or nothing. Dr Bleakley described how, in this context, they worked hard to diagnose children and to get them medical treatment, and if they improved then this course of action was deemed successful.

Present-day context of ADHD

Dr Bleakley explained how much has changed since then, and emphasised that these days, ADHD is clearly recognised as a lifespan condition. This can mean that once a child is diagnosed, the clinician may reach out to the parents and grandparents in case they have the disorder themselves but have gone undiagnosed. Additionally, girls with ADHD are now being recognised, although the approach to diagnosis has had to change through asking different questions. For instance, girls may compensate and function very well at school but have behavioural problems at home. As time passes, their compensatory mechanisms may be overcome by their symptoms and problems may start at school too. Dr Bleakley highlighted that generally, clinicians understand a great deal more about ADHD these days.

Current treatment of ADHD

Dr Bleakley then described the phrases that may be heard now in a modern-day service, such as ‘psychoeducation’ and ‘build resilience’, the latter of which she believes to be at the heart of the work they do. She expanded on this by explaining that a solid foundation must be laid using psychoeducation before a child can be medically optimised. She stated that, in her opinion, psychoeducation is an important step to enable the individual and their family to understand what elements of the patient’s behaviour profile ‘belong’ to ADHD and what elements may relate to other comorbid conditions, so that ADHD medication is not expected to alter all behaviours. Dr Bleakley emphasised that it is also important to draw out the individual’s strengths, for their own self-confidence moving forwards. Dr Bleakley recounted her experience at an advisory board meeting with other clinicians to discuss optimising ADHD management. Although each clinician had their own pathway to diagnosing and treating ADHD, they all agreed that laying a foundation using psychoeducation and drawing out the individual’s strengths were the most important aspects.

Evidence for optimising ADHD treatment

In the next part of her presentation, Dr Bleakley presented research into optimising treatment of ADHD. She introduced the Multimodal Treatment of ADHD (MTA) Cooperative Group study, which looked at 579 children with ADHD aged 7–9.9 years, with an initial 14-month follow-up design.41 The children could be split into four groups based on the treatment they were receiving: intensive medication management (n=144), intensive behavioural treatment (n=144), a combination of these (n=145) or standard community care (n=145). This study concluded that those who received intensive medication management had superior outcomes compared with those receiving only behavioural treatment or routine community care. Combined treatment did not have significantly greater benefits than medication management for core ADHD symptoms, but may have provided advantages for non-ADHD symptoms and positive functioning. Building on this, Dr Bleakley went on to discuss differential response to treatment, highlighting a study of 174 people with ADHD, which found that 87% of patients had a clinical response to MPH and/or amfetamine.29

Dr Bleakley then described the Dundee ADHD Clinical Care Pathway, which was developed to promote effective management of ADHD through structured reassessment.42 The pathway was primarily nurse-led, and involved referral and pre-assessment via a telephone interview before a standard face-to-face interview and physical examination in the assessment stage. Following pre-assessment interviews, a senior clinician would meet with the family to review the information with them, discuss the diagnosis and develop a treatment plan. For those patients who were initiated on pharmacological treatment for their ADHD, they would attend a 4-week structured dose-optimisation period, whereby titration appointments were conducted face to face or by telephone. In addition to clinical feedback from the patient and parent/carer, benchmarking tools such as the Swanson Nolan and Pelham Rating Scale IV (SNAP-IV) and ADHD Rating Scale IV were used to measure the efficacy of the treatment. Once a patient reached dose optimisation, patients attended ‘continuing care clinics’ to monitor and adjust their ADHD treatments.42 Dr Bleakley stated that although there isn’t a universally agreed definition of ‘optimal management of ADHD’,  the following three points should always be considered when treating patients with ADHD: 1) the level of ADHD symptoms and functional impact should be reduced; 2) quality of life should be improved; and 3) symptom benefits should outweigh unwanted effects.8,43,44

Importance of optimisation: ADHD and mortality

Dr Bleakley went on to emphasise the importance of optimising the treatment of ADHD in order to prevent negative outcomes. To emphasise this, she referred to data from a Danish national registry study which follows 1.92 million individuals from their first birthday through to 2013, among whom 32,061 individuals had ADHD. Results from the study highlighted that during follow-up of those 1.92 million individuals, the mortality rate was doubled for those patients with ADHD vs those without.45

Dr Bleakley’s clinical guidelines

Dr Bleakley went on to describe her own clinical experience of diagnosis and treatment, which involves: 1) clinical interview; 2) classroom observation by an ADHD nurse (a functional assessment); 3) questionnaires (the Conners questionnaire is used during diagnosis as it is useful for diagnosing girls, and the SNAP questionnaire is used for follow-up); and 4) if needed, a computerised test of attention and activity (Qb test) is conducted. Dr Bleakley described how, in most cases, these assessments all fit together to give a clear diagnosis of ADHD. She explained that in her clinic, they largely follow the evidence-based guidance from the NICE guidelines.7 Dr Bleakley drew particular attention to where the NICE guidelines highlight the importance of psychoeducation following a diagnosis of ADHD, through structured discussions with the patient themselves (and family/carers if appropriate). The discussion surrounding how ADHD will affect their life should be balanced and include information on the positive impacts of receiving a diagnosis such as improving their understanding of symptoms, identifying and building on individual strengths and improving access to services, as well as the negative impacts, such as labelling and stigma, education issues, employment issues and social relationship issues.7 This discussion should also inform the shared treatment plan.

With regards to specific pharmacological treatments for the short-term treatment of ADHD, Dr Bleakley discussed the recent systematic review and network meta-analysis by Dr Cortese, which provides evidence to support the first-line use of MPH in children and adolescents, and amfetamines in adults.46 She related this back to the NICE guidelines of treatment medications, which state that MPH should be offered as first-line pharmacological treatment for children and adolescents, and that LDX or MPH should be offered as first-line pharmacological treatment for adults with ADHD.7

In the final part of her presentation, Dr Bleakley concluded that to support children and young people with ADHD, patients first need to understand their ADHD and identify their strengths, and should be involved in their treatment plan.

Dr Bleakley: “We need to involve that child or young person in their treatment plan, and make sure that we are speaking directly to them”

Clinical Hot Topic 9: Misuse of stimulants in ADHD clinical practice

Dr Lotta Borg Skoglund (Senior Consultant Psychiatrist, Uppsala University, Uppsala, Sweden) discussed the non-medical use of stimulant medication.

Dr Skoglund explained that stimulant medications are effective in ADHD by affecting the dopaminergic system, which is the same system that is affected when you develop addiction and substance-use disorders.47,48 She also noted that individuals with ADHD are at a much higher risk of developing substance-use disorders if they don’t get the right assessment, diagnosis or proper treatment.

Dr Skoglund went on to explain that diversion or misuse of stimulant medication is a problem; for example, in the USA in 2016, approximately 1.4 million individuals (aged ≥12 years) reported initiating non-medical use of stimulants, and this was most common in adults aged 18–25 years.49 When this was broken down, individuals who reported non-medical use of stimulants had higher levels of ADHD symptoms, had harmfully used or were addicted to other substances, or had eating disorders.49 The majority of the individuals obtained the non–medical-use stimulant from their family or friends (~50–90%), or it was their own prescription (4–35%).49 The study also investigated the reasons why individuals with ADHD misused stimulants. The main reasons were: issues surrounding academic failure (50–89% of college students); to increase productivity (40% of adults); for recreational purposes (2–31% of college students); curiosity (17–31% of college students); for self-medication of undiagnosed ADHD (4–12%); or to lose weight (3.5–11.7%).49 Dr Skoglund went on to explain that non-medical use of stimulants is a risk not only for the individual but also for society in general, and can lead to the following: worse academic outcomes; adverse effects, which have not been discussed with them and for which they will have received no clinical guidance; increased costs for emergency visits and intensive care; cardiac failure (since the individual would not have not been screened for cardiac malfunction or congenital disorders, as they would have been if a physician had prescribed them stimulants); serious intoxication; and death.49

Dr Skoglund went on describe how, in her clinical practice, she minimises risks for non-medical use of stimulants in individuals with ADHD. She emphasised that is the duty of the clinician to explain to the individual and their families the legal and medical risks of misusing stimulants or giving them to others. Additionally, from her own clinical experience, she felt that clinicians should take the individual with ADHD through different processes of how to say “no” to individuals who may pressure them to let them try their prescribed stimulant. Dr Skoglund noted that there is the possibility of considering different formulations when treating individuals with ADHD who are at risk of non-medical use of treatments; for example, modified-release stimulants or, where applicable, non-stimulants. Dr Skoglund went on to describe that in her clinical practice, she works with the patient to develop a ‘treatment contract’ with common agreements between her and her patient on how to build and follow his or her individual treatment plan. Within this contract, she will include expedition intervals because she wouldn’t want to send large amounts of stimulant medication into, for example, a public setting such as a school or college.

Overall, Dr Skoglund stated that individuals with ADHD who are correctly diagnosed, and in her clinical experience, correctly treated for their ADHD have an increased quality of life, higher self-esteem, functioning and productivity.

Dr Skoglund: “In my clinical practice, I try to form an alliance and, within that alliance, draw up a treatment contract with common agreements between me and my patient on how to build and follow his or her individual treatment plan”

  1. Beheshti A, Chavanon M-L, Christiansen H. Emotion dysregulation in adults with attention deficit hyperactivity disorder: a meta-analysis. BMC Psychiatry 2020; 20: 120.
  2. Kollins SH, DeLoss DJ, Cañadas E, et al. A novel digital intervention for actively reducing severity of paediatric ADHD (STARS-ADHD): a randomised controlled trial. Lancet Digit Health 2020; 2: e168-e178.
  3. López-Pinar C, Martínez-Sanchís S, Carbonell-Vayá E, et al. Efficacy of nonpharmacological treatments on comorbid internalizing symptoms of adults with attention-deficit/hyperactivity disorder: a meta-analytic review. J Atten Disord 2020; 24: 456-478.
  4. Caye A, Agnew-Blais J, Arseneault L, et al. A risk calculator to predict adult attention-deficit/hyperactivity disorder: generation and external validation in three birth cohorts and one clinical sample. Epidemiol Psychiatr Sci 2019; 29: e37.
  5. Cortese S. Pharmacologic treatment of attention deficit-hyperactivity disorder. N Engl J Med 2020; 383: 1050-1056.
  6. Chen VC-H, Chan H-L, Wu S-I, et al. Methylphenidate and mortality in children with attention-deficit hyperactivity disorder: population-based cohort study. Br J Psychiatry 2020; Epub ahead of print.
  7. NICE guideline 2018. Attention deficit hyperactivity disorder: diagnosis and management. Available at: https://www.nice.org.uk/guidance/ng87. Accessed November 2019.
  8. Taylor E, Döpfner M, Sergeant J, et al. European clinical guidelines for hyperkinetic disorder — first upgrade. Eur Child Adolesc Psychiatry 2004; 13(Suppl 1): I/7-I/30.
  9. Daley D, van der Oord S, Ferrin M, et al. Behavioral interventions in attention-deficit/hyperactivity disorder: a meta-analysis of randomized controlled trials across multiple outcome domains. J Am Acad Child Adolesc Psychiatry 2014; 53: 835-847.
  10. Steiner NJ, Frenette EC, Rene KM, et al. In-school neurofeedback training for ADHD: sustained improvements from a randomized control trial. Pediatrics 2014; 133: 483-492.
  11. Meisel V, Servera M, Garcia-Banda G, et al. Neurofeedback and standard pharmacological intervention in ADHD: a randomized controlled trial with six-month follow-up. Biol Psychol 2013; 94: 12-21.
  12. 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.
  13. Cairncross M, Miller CJ. The effectiveness of mindfulness-based therapies for ADHD: a meta-analytic review. J Atten Disord 2020; 24: 627-643.
  14. Young S, Amarasinghe JM. Practitioner Review: Non-pharmacological treatments for ADHD: a lifespan approach. J Child Psychol Psychiatry 2010; 51: 116-133.
  15. Canadian ADHD Resource Alliance (CADDRA). Canadian ADHD Practice Guidelines. 4.1. Toronto, ON: CADDRA, 2020.
  16. Young S, Smith J. Helping Children with ADHD: A CBT Guide for Practitioners, Parents and Teachers. West Sussex, UK: John Wiley & Sons, Ltd, 2017.
  17. Young S, Bramham J. Cognitive-Behavioural Therapy for ADHD in Adolescents and Adults: A Psychological Guide to Practice. Second Edition. West Sussex, UK: John Wiley & Sons, Ltd., 2012.
  18. Stahl SM, Mignon L. Stahl’s Illustrated Attention Deficit Hyperactivity Disorder. New York, NY: Cambridge University Press, 2009.
  19. Arnsten AFT, Rubia K. Neurobiological circuits regulating attention, cognitive control, motivation, and emotion: disruptions in neurodevelopmental psychiatric disorders. J Am Acad Child Adolesc Psychiatry 2012; 51: 356-367.
  20. Huss M, Chen W, Ludolph AG. Guanfacine extended release: a new pharmacological treatment option in Europe. Clin Drug Investig 2016; 36: 1-25.
  21. Novartis Pharmaceuticals UK Ltd. Ritalin Summary of Product Characteristics. Last updated April 2018.
  22. Novartis Pharmaceuticals Corporation. Ritalin LA US Prescribing Information. 2017.
  23. González MA, Pentikis HS, Anderl N, et al. Methylphenidate bioavailability from two extended-release formulations. Int J Clin Pharmacol Ther 2002; 40: 175-184.
  24. Haessler F, Tracik F, Dietrich H, et al. A pharmacokinetic study of two modified-release methylphenidate formulations under different food conditions in healthy volunteers. Int J Clin Pharmacol Ther 2008; 46: 466-476.
  25. Boellner SW, Stark JG, Krishnan S, et al. Pharmacokinetics of lisdexamfetamine dimesylate and its active metabolite, d-amphetamine, with increasing oral doses of lisdexamfetamine dimesylate in children with attention-deficit/hyperactivity disorder: a single-dose, randomized, open-label, crossover study. Clin Ther 2010; 32: 252-264.
  26. Ermer JC, Adeyi BA, Pucci ML. Pharmacokinetic variability of long-acting stimulants in the treatment of children and adults with attention-deficit hyperactivity disorder. CNS Drugs 2010; 24: 1009-1025.
  27. Montoya A, Hervas A, Cardo E, et al. Evaluation of atomoxetine for first-line treatment of newly diagnosed, treatment-naïve children and adolescents with attention deficit/hyperactivity disorder. Curr Med Res Opin 2009; 25: 2745-2754.
  28. Polanczyk GV, Willcutt EG, Salum GA, et al. ADHD prevalence estimates across three decades: an updated systematic review and meta-regression analysis. Int J Epidemiol 2014; 43: 434-442.
  29. Arnold LE. Methylphenidate vs. amphetamine: comparative review. J Atten Disord 2000; 3: 200-211.
  30. Hodgkins P, Shaw M, Coghill D, et al. Amfetamine and methylphenidate medications for attention-deficit/hyperactivity disorder: complementary treatment options. Eur Child Adolesc Psychiatry 2012; 21: 477-492.
  31. Zhu H-J, Patrick KS, Yuan H-J, et al. Two CES1 gene mutations lead to dysfunctional carboxylesterase 1 activity in man: clinical significance and molecular basis. Am J Hum Genet 2008; 82: 1241-1248.
  32. Patrick KS, Straughn AB, Minhinnett RR, et al. Influence of ethanol and gender on methylphenidate pharmacokinetics and pharmacodynamics. Clin Pharmacol Ther 2007; 81: 346-353.
  33. Srinivas NR, Hubbard JW, Korchinski ED, et al. Enantioselective pharmacokinetics of dl-threo-methylphenidate in humans. Pharm Res 1993; 10: 14-21.
  34. Lyauk YK, Stage C, Bergmann TK, et al. Population pharmacokinetics of methylphenidate in healthy adults emphasizing novel and known effects of several carboxylesterase 1 (CES1) variants. Clin Transl Sci 2016; 9: 337-345.
  35. Merali Z, Ross S, Paré G. The pharmacogenetics of carboxylesterases: CES1 and CES2 genetic variants and their clinical effect. Drug Metabol Drug Interact 2014; 29: 143-151.
  36. Pennick M. Absorption of lisdexamfetamine dimesylate and its enzymatic conversion to d-amphetamine. Neuropsychiatr Dis Treat 2010; 6: 317-327.
  37. Pennick M. Metabolism of the prodrug lisdexamfetamine dimesylate in human red blood cells from normal and sickle cell disease donors. J Drug Assess 2013; 2: 17-20.
  38. Ermer J, Homolka R, Martin P, et al. Lisdexamfetamine dimesylate: linear dose-proportionality, low intersubject and intrasubject variability, and safety in an open-label single-dose pharmacokinetic study in healthy adult volunteers. J Clin Pharmacol 2010; 50: 1001-1010.
  39. Wang G-J, Volkow ND, Wigal T, et al. Long-term stimulant treatment affects brain dopamine transporter level in patients with attention deficit hyperactive disorder. PLoS One 2013; 8: e63023.
  40. Swanson J, Gupta S, Lam A, et al. Development of a new once-a-day formulation of methylphenidate for the treatment of attention-deficit/hyperactivity disorder: proof-of-concept and proof-of-product studies. Arch Gen Psychiatry 2003; 60: 204-211.
  41. MTA Cooperative Group. A 14-month randomized clinical trial of treatment strategies for attention-deficit/hyperactivity disorder. Arch Gen Psychiatry 1999; 56: 1073-1086.
  42. Coghill D, Seth S. Effective management of attention-deficit/hyperactivity disorder (ADHD) through structured re-assessment: the Dundee ADHD Clinical Care Pathway. Child Adolesc Psychiatry Ment Health 2015; 9: 52.
  43. Remschmidt H, Global ADHD Working Group. Global consensus on ADHD/HKD. Eur Child Adolesc Psychiatry 2005; 14: 127-137.
  44. Canadian ADHD Resource Alliance (CADDRA). Canadian ADHD Practice Guidelines. Fourth Edition. Toronto, ON: CADDRA, 2018.
  45. Dalsgaard S, Østergaard SD, Leckman JF, et al. Mortality in children, adolescents, and adults with attention deficit hyperactivity disorder: a nationwide cohort study. Lancet 2015; 385: 2190-2196.
  46. Cortese S, Adamo N, Del Giovane C, et al. Comparative efficacy and tolerability of medications for attention-deficit hyperactivity disorder in children, adolescents, and adults: a systematic review and network meta-analysis. Lancet Psychiatry 2018; 5: 727-738.
  47. Volkow ND, Wang G-J, Tomasi D, et al. Methylphenidate-elicited dopamine increases in ventral striatum are associated with long-term symptom improvement in adults with attention deficit hyperactivity disorder. J Neurosci 2012; 32: 841-849.
  48. Tarter RE, Ammerman RT, Ott PJ. Handbook of Substance Abuse: Neurobehavioral Pharmacology. New York, NY: Springer Science & Business Media, 2013.
  49. Faraone SV, Rostain AL, Montano CB, et al. Systematic Review: Nonmedical use of prescription stimulants: risk factors, outcomes, and risk reduction strategies. J Am Acad Child Adolesc Psychiatry 2020; 59: 100-112.