Clinical Hot Topic 10: ADHD and autism spectrum disorders: clinical diagnosis, overlap, and implications for treatment

Professor Jan Buitelaar (Professor of Psychiatry and Child & Adolescent Psychiatry, Radboud University Medical Centre, Nijmegen, The Netherlands) discussed the overlap between the symptoms of ADHD and autism spectrum disorder (ASD). He discussed how there are numerous factors that can affect developmental outcome from birth, such as environmental influences, genetic predispositions, maturation and behaviour. Additionally, he suggested that early support from the family of a child with ADHD or ASD may have a protective effect on the child’s development. However, there may be adverse environmental influences that may negatively impact the child’s development.

Professor Buitelaar moved on to discuss the concept of compensation in neurodevelopmental disorders. He discussed how the more severe the neurodevelopmental symptoms, the more the individual has to compensate.1 Professor Buitelaar suggested that compensatory behaviours (plasticity changes, cognitive compensation, adaptation) may mask the primary deficits. For example, an individual may have severe neurodevelopmental symptoms; however, if they are able to achieve a high degree of compensation, they may appear to not meet diagnostic criteria for a neurodevelopmental disorder.1

Clinical characteristics and overlap between ADHD and ASD

Professor Buitelaar stated that based on the core symptoms of ADHD (inattention and impulsivity/hyperactivity) and ASD (social-communication deficits, fixated interests, repetitive behaviours and abnormal sensory processing),2 a clear overlap between the two disorders may not be apparent. However, when the broader symptoms of ADHD are examined, such as problems with social communication, cognitive impairments and emotional lability,3 these are comparable with the broader symptoms of ASD, such as hyperactivity, emotional lability, intellectual disability and irritability.4 Consequently, there is a noticeable symptom overlap between the two disorders.

Increased emotional lability is observed in both ADHD and ASD. However, Professor Buitelaar described how irritability may be more episodic in individuals with ADHD compared with individuals with ASD, who may exhibit chronic irritability. Inappropriately positive emotions, on the other hand, are present in both ADHD and ASD.5 However persistent anger, impulsive aggression, argumentative or defiant behaviour, and vindictiveness are not typically observed in ADHD and ASD, unlike other psychiatric disorders (e.g. oppositional defiant disorder and intermittent explosive disorder) that may be comorbid with either ADHD or ASD.5

Furthermore, from Professor Buitelaar’s own clinical observations, he had noticed that when an individual is diagnosed with a neurodevelopmental disorder such as ASD, a sibling or other family member may also have the same or a similar disorder, such as ADHD, dyslexia or social problems. This observation is supported by evidence that some children with ASD have ADHD symptoms that may require clinical treatment.6 Additionally, some children with ADHD have severe social disability and/or mild ASD symptoms.6-9 Possible theoretical models for the overlap between ADHD and ASD symptoms include: (1) there is one overarching disorder; (2) they share a common risk factor (genetic or environmental); or (3) there is a common neurobiological substrate.10

Assessment issues

In Professor Buitelaar’s opinion, clinicians may miss a diagnosis of ASD or ADHD depending on which disorder was diagnosed first. For example, there is large phenotypic variation across the spectrum of ASD, which may mask ADHD symptoms that could be present, such as11:

  • Intellectual level
  • Verbal ability
  • Social skills
  • Repetitive or stereotyped behaviour and interests
  • Presence, type and degree of sensory and motor differences
  • Developmental course
  • Presence of comorbid medical issues, such as seizures or gastrointestinal problems
  • Severity and type of comorbid psychiatric conditions.

Additionally, Professor Buitelaar suggested that parents and clinicians may miss underlying ASD symptoms in a child with ADHD due to the child reaching developmental milestones or due to diagnostic overshadowing. He explained that a child may present with clear characteristics of another disorder separate from their original diagnosis, but the clinician may attribute the comorbid symptoms to the primary disorder. Furthermore, the high intellectual ability of a child may have allowed them to work around the challenges up until their ability to adapt is exceeded, at which point other symptoms may become clearer. In addition, a diagnosis of ASD could be missed if a child: (1) has a clear desire to interact socially, despite their social skills being poor; (2) lacks certain behavioural signs such as repetitive movements; (3) is not particularly disruptive, which may be common in girls; or (4) has learned to mask certain symptoms or to avoid problematic situations. Professor Buitelaar also noted that a diagnosis of ASD could be missed due to a lack of clinical expertise. He then went on to state that for clinicians to accurately diagnose psychiatric comorbidities in individuals with ADHD, they must collect information that covers both present and historical symptoms, using various methods from multiple informants. Clinicians should also recognise that an older person with ASD will present differently than a child with ASD, due to the differences in developmental level and experience.

Treatment implications

Professor Buitelaar suggested that recognising the overlap between ADHD and ASD should enable integration of research of the two disorders. Also, recognition should allow for application of theories and research approaches in ASD to ADHD and vice versa. Professor Buitelaar noted that at his own centre, they have now combined the clinics for ASD and ADHD to enable optimal diagnosis, management and treatment of both disorders. He stated that the aims and objectives of treatment for neurodevelopmental disorders should be to: reduce primary and comorbid symptoms; reduce risk of further complications; educate the individual and their family about the disorder; adapt the environment to the individual’s needs; enhance the coping skills of the individual, their family and teachers; and change maladaptive views. Overall, he stated that treatment of neurodevelopmental disorders should be ‘more care than cure’.

Professor Buitelaar: “Identify toxic views of autism and ADHD … we should probe for these and try to detoxify them”

Clinical Hot Topic 11: ADHD and personality disorders

Professor J Antoni Ramos-Quiroga (Professor of Psychiatry & Clinical Psychiatry, Vall d’Hebron University Hospital, Barcelona, Spain) began his presentation by explaining the importance of screening for ADHD in those with personality disorders, due to the high rate of comorbidity between the two disorders. He further described how acknowledging that ADHD is a chronic disorder, which affects people across the lifespan,12 is essential and useful for clinicians in diagnosing ADHD in those with personality disorders.

Overlap of ADHD and personality disorders

Professor Ramos-Quiroga then expanded on the commonalities of ADHD and personality disorders. He noted that both personality disorders and ADHD begin in early in childhood, remain stable or chronic throughout the lifespan, and symptoms are consistent in different situations.2,13 Professor Ramos-Quiroga described the overlap of symptoms between certain personality disorders and ADHD. Similar to ADHD, the symptoms of borderline personality disorder (BPD) include impulsivity, difficulties in emotional regulation and interpersonal instability. Furthermore, symptoms of histrionic personality disorder include dramatic expression of emotion and suggestibility, whereas symptoms of dependent personality disorder include difficulties in assuming responsibility, autonomy and difficulty in initiating activities, which are similar to those expressed in ADHD.14 In addition, narcissistic personality disorder and Cluster B personality disorders have been found to correlate with ADHD-hyperactive subtype, and likewise Cluster C personality disorders have correlated with the ADHD-inattentive subtype.15 Cluster B personality disorders include antisocial, borderline, histrionic and narcissistic personality disorders, and Cluster C includes avoidant, dependent, obsessive-compulsive, passive-aggressive and depressive personality disorders.15

Adult ADHD and personality disorders

Professor Ramos-Quiroga next described a study that found 16.1% of women with BPD had severe adult ADHD. Adult ADHD was associated with a greater likelihood of Axis I and Axis II disorders, including specific phobias and somatisation, panic disorder, anorexia nervosa, paranoid personality disorder and elements of schizoid and dependent personality disorder.16 He built on these findings using evidence from another study, which found adult female prison inmates with ADHD showed an increased prevalence of avoidant personality disorder in comparison with those without ADHD (54.5% vs 28.9%).17

Childhood ADHD and personality disorders

Professor Ramos-Quiroga explained how another important aspect for clinicians is whether a history of ADHD in childhood is a risk factor for a personality disorder in adulthood. He described a study which found that adults with a history of childhood ADHD behaviours were at a higher risk of being diagnosed with antisocial, histrionic, narcissistic (Cluster B), schizoid and schizotypal (Cluster A) personality disorders in later life than adults without.18 He went on to report the results of a similar study, which found a higher comorbidity of childhood hyperactivity and personality disorders at a mean age of 20–21 years, in comparison with a community control group. The most common personality disorders were histrionic (12%), antisocial (21%), passive-aggressive (18%) and BPD (14%).19 Professor Ramos-Quiroga also presented data which showed that for girls aged 6–18 years with ADHD, the lifetime risk for developing antisocial disorders is >7-times higher than for those without ADHD (hazard ratio 7.2; 95% confidence interval [CI] 4.0–12.7; p<0.001).20 He continued to describe how when reviewing the subcortical structures related to ADHD, the amygdala is a brain structure whose dysfunction is correlated with ADHD and emotional difficulties.21 Professor Ramos-Quiroga suggested that the amygdala could also be affected in personality disorders too.

Borderline personality disorder and ADHD

Professor Ramos-Quiroga next emphasised how adults with ADHD exhibit higher levels of emotional lability compared with those without ADHD. For example, research into the discriminative value of emotional lability in the diagnosis of ADHD in adults found that levels were higher for those with ADHD versus clinical (those with psychiatric disorders not including ADHD, e.g. depression) and community controls.22 Professor Ramos-Quiroga then introduced research which investigated the presence of comorbidities in people with BPD versus those with both ADHD and BPD. Individuals with BPD had significantly more anxiety disorders (78.6% vs 56.5%; p=0.002) and mood disorders (62.5% vs 37.7%; p=0.001) than individuals with both BPD and ADHD. On the other hand, individuals with both BPD and ADHD had significantly more substance-abuse disorders (59.4% vs 38.4%; p=0.006) as comorbidities than individuals with BPD. The presence of avoidant personality disorder (categorised as a Cluster C personality disorder) was more frequently reported in those with BPD than those with ADHD and BPD (33% vs 0%; p<0.001). Finally, the risk of suicidal behaviours was significantly more common in those with both ADHD and BPD than those with BPD (72.9% vs 54.5%; p=0.009).23

The alternative five-factor model

Professor Ramos-Quiroga then stated that it is important that in each individual with ADHD, their normal personality profile is assessed. One of the instruments that can be used for this is the Zuckerman–Kuhlman Personality Questionnaire (ZKPQ), which is based on the alternative five-factor model of personality. Professor Ramos-Quiroga noted that in his centre, his research group are studying the capacity of the ZKPQ to differentiate between people with ADHD and those without. Some of the traits upon which people with ADHD can be distinguished from those without include having higher scores for neuroticism–anxiety (p=0.001), impulsivity (p<0.0005) and general activity (p<0.0005). Logistic regression analysis found it to be a statistically significant model (X24=238; p=0.0005) with an odds ratio of 10.7 for distinguishing people with ADHD based on these traits.24

Treating ADHD in people with both ADHD and BPD

Professor Ramos-Quiroga introduced a clinical trial, named Treatment of Impulsivity in Adults with Probiotics (PROBIA; NCT03495375). A total of 180 individuals aged 18‒65 years with ADHD and/or BPD are to be randomised to receive either placebo (n=90) or the probiotic (n=90) for 10 weeks, to test its efficacy for treating symptoms of impulsivity. Recruitment for this trial is expected to be completed by 1 April 2021.25

In the final part of his session, Professor Ramos-Quiroga concluded that ADHD shares some features with personality disorders such as BPD.14 He noted that one hypothesis for this correlation may be that ADHD is a precursor to personality disorders.18,19 He added that the prevalence of personality disorders in adults with ADHD is high, in particular Cluster B personality disorders.15,18,19 Furthermore, when taking into account dimensions and traits using the ZKPQ, predictors of adult ADHD are neuroticism–anxiety, impulsivity and general activity.24 In Professor Ramos-Quiroga’s opinion, patients seeking treatment for personality disorders should be evaluated for ADHD and receive the appropriate treatment after a diagnosis has been confirmed.

Professor Ramos-Quiroga: “In all the patients seeking treatment for personality disorders, it is absolutely necessary to assess and screen for ADHD”

Behavioural addictions

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

Professor Dan Stein (Professor & Chair of the Department of Psychiatry & Mental Health, University of Cape Town, Cape Town, South Africa) started his session by discussing the growing area of behavioural addictions. He highlighted the following proposed behavioural addictions: gambling and gaming disorders, internet, smartphone, sexual, exercise, food and tango addictions. He continued that, in his opinion, there is a growing prevalence of behavioural addictions following the invention of social media. However, he suggested that there are not enough rigorous data to confirm this, and evidence for how to provide treatment for individuals who may have a behavioural addiction is limited.

Professor Stein discussed how, in his opinion, gambling addictions are the only behavioural addictions with rigorous data on prevalence. Evidence from the National Comorbidity Survey of 9282 adults noted that 78% of US households had gambled during their lifetime,26 while 2.3% of households had gambling problems within their lifetime, and 0.6% of households had a history of pathological gambling.26 However, Professor Stein stated that although he feels this may be the only example of rigorous data on prevalence of behavioural addictions, there are plenty of suggestive data. A systematic review and meta-analysis of the prevalence of internet addiction (113 studies; n=693,306 individuals) suggested that the average lifetime prevalence of generalised internet addiction was 7.02%; the study also noted that the prevalence of internet gaming disorder was 2.47%.27

Professor Stein moved on to describe the ‘catch-22’ of ‘unlabelling’ in relation to sexual addiction, which is not currently in the official classification guidelines for psychiatric disorders. Results from a systematic review found that although there are increasing numbers of studies pertaining to compulsive sexual behaviours, much of the research is compounded by simple methodological designs, a lack of theoretical integration and an absence of quality measurements.28 In Professor Stein’s opinion, because sexual addiction is not labelled as a psychiatric disorder, there are no agreed-upon diagnostic criteria and clinicians are not able to study the addiction rigorously. On the other hand, Professor Stein noted that there may also be a reluctance of the official associations to consider sexual addiction as a psychiatric disorder, as it is perceived as part of normal life.

Considering a new disorder

Professor Stein the considered what criteria allow for the labelling of a psychiatric disorder. Key points included: a behavioural or psychological syndrome within an individual; consequences including clinically significant distress or disability; no expectable response to common stressors and losses.29

Importance of screening

Professor Stein discussed that screening is important for the diagnosis of individuals with behavioural addictions, and that development of official guidelines would aid the production of accurate screening tools and methods. For example, as of 2020, data have shown that there were 32 tools for gaming disorder; however, no single screening tool is considered optimal.30


Professor Stein went on to discuss the A-B-C model of psychobiology of behavioural addictions. Prior to discussing this topic, he stated that this entails some neuromythology. ‘A’ refers to ‘affect’; Professor Stein observed that behavioural addiction is associated with anxiety and depression, and clinicians typically target this portion of the neurocircuitry when treating behavioural addictions.31 ‘B’ refers to behavioural addiction, which, by definition, is an addiction. Professor Stein suggested that the reward system neurocircuitry could be targeted with dopaminergic or opioid agents. For example, one systematic review showed an association between gambling disorder and dopaminergic receptor alterations, as well as dysfunctions in presynaptic dopamine trafficking, which is suggestive of hyperdopaminergic states.32 Finally, ‘C’ refers to cognitive control; Professor Stein suggested that behavioural addictions are characterised by impulsivity, and so treatment should target the prefrontal–subcortical control neurocircuitry with glutamatergic agents.31,33 He provided evidence for behavioural addictions affecting these brain regions, using results from a meta-analysis of neurocognitive response tasks completed by individuals with gaming disorder.34 This meta-analysis found that individuals with gaming disorder had impaired response inhibition compared with individuals without gaming disorder.34


In Professor Stein’s clinical opinion, cognitive behavioural therapy (CBT) should be a part of the treatment plan for individuals who are pathological gamblers. CBT components may include:

  • Education or motivational enhancement
  • Financial or trigger planning
  • Behavioural interventions
  • Imaginal exposure
  • Cognitive therapy of relevant beliefs
  • Relapse prevention
  • Family involvement.

The Cochrane review of CBT treatment for pathological gamblers comprised of 11 studies which compared the use of CBT with control (either no treatment, Gamblers Anonymous referral or non-specific treatment).35 Only one of the included studies showed no effect of CBT treatment; four studies, which used motivational interviewing, suggested a reduction in financial loss, and one study indicated that there were short-term effects of a 12-step group therapy programme. However, there was little information on the long-term effects of CBT.35 A separate meta-analysis determined there was a significant effect of CBT on treating problem gambling over a 24-month period.36 Another meta-analysis of brief personalised feedback interventions for problem gambling noted a significant effect of personalised feedback interventions to reduce problem gambling behaviours.37

Professor Stein stated that there is limited effectiveness of psychotherapy for the treatment of internet gaming disorder or addiction.38 This finding is supported by statements from a systematic review which investigated treatments of internet gaming disorder (13 studies) and internet addiction (13 studies).38 The authors of the review concluded that these studies were limited by methodological flaws and a lack of consistent definitions and measures.38 These findings suggested there is currently limited evidence of the effectiveness of any treatment for internet gaming disorder and internet addiction.38 Professor Stein next provided evidence that exercise may be a possible therapy for individuals with a smartphone addiction.39 A systematic review and meta-analysis of nine randomised controlled trials highlighted the significant positive effects of exercise for individuals who had more severe symptoms of smartphone addiction, particularly for exercise programmes running for ≥12 weeks.39


Professor Stein stated that, in his opinion, pathological gambling is one of the only behavioural addictions where there is evidence that pharmacotherapy may be effective. He provided data from a meta-analysis of 34 studies (n=1340) which showed that pharmacotherapy reduced global severity (effect size = 1.35), frequency (effect size = 1.22) and financial loss (effect size = 0.8) in those with gambling disorder.40 However, when the controlled studies were examined, the effect sizes were significantly smaller for the reduction in global severity (effect size = 0.41), frequency (0.11) and financial loss (0.22).40

Public health issues

Finally, Professor Stein covered public health issues that surround behavioural addictions. He stated that researchers are a long way off understanding the precise psychobiology of these disorders. Additionally, public health interventions are key to the prevention of substance-use disorders and behavioural addictions.41

Professor Stein concluded his presentation with some key points:

  • Behavioural addictions are increasingly important.
  • Classification or conceptualisation is a matter that is still debated.
  • There is some progress in the treatment of behavioural addictions using medication and psychotherapy.

There is a public health battle that remains to be fought.

Professor Stein: “There seems to be a growing prevalence of these [behavioural] addictions post-development of the internet and social media”

ADHD and comorbid substance-use disorders

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

Dr Lotta Borg Skoglund (Senior Consultant Psychiatrist, Uppsala University, Uppsala, Sweden) initially discussed the background and epidemiology of ADHD and psychiatric comorbidity in adults. She stated that one study showed that adults with ADHD typically had >1 comorbid psychiatric disorder (51.7%).42 In a separate study, which investigated the prevalence of ADHD in adult psychiatric outpatients, the most frequent comorbid psychiatric diagnosis in individuals diagnosed with ADHD was depression (48.9%).43 Additionally, substance abuse (30.8%) and substance dependence (24.4%) were also shown to be common comorbid psychiatric conditions in adults with ADHD.43

Dr Skoglund moved on to highlight that substance-use disorders (SUDs) occur in 15.2% of the adult ADHD population, compared with 5.6% in the general population.44 Furthermore, another study found that adolescents with ADHD are more likely to take risks and experiment with alcohol and drugs earlier than adolescents without ADHD.45 ADHD was also associated with more severe addictions; the addictions tended to be more chronic and led to greater impairment.45 Dr Skoglund discussed that 60% of adolescents with SUDs typically fulfil diagnostic criteria for another psychiatric disorder and have a poor lifetime prognosis (premature death, physical and mental illness, substance misuse, criminal convictions and poverty).46,47 She highlighted that there are many studies that provide evidence that ADHD and SUD both involve genetic and environmental factors.48-52

Furthermore, Dr Skoglund indicated that adults may remain un- or misdiagnosed with ADHD due to a variety of reasons. These may include a lack of recognition of ADHD in adulthood, symptoms of ADHD in children are very different to those observed in adults, and adults with ADHD can adjust their behaviour to cope with their symptoms and so appear ‘normal.’2,53,54 Finally, she suggested that, as other psychiatric comorbidities can hide or mask ADHD symptoms, it is the job of the clinician to untangle which are ADHD symptoms and which are symptoms of a comorbidity.53,54

Assessment and treatment of ADHD and comorbid SUD

Dr Skoglund provided her own clinical experience of some of the reasons that may cause underdiagnosis or overdiagnosis of ADHD. She stated that reasons for underdiagnosis may include: missing childhood history of ADHD symptoms that are required for a complete ADHD diagnosis; difficulties with differentiating between executive dysfunction and a chaotic lifestyle caused by SUD; and ADHD symptoms potentially being masked by comorbidity or mistaken for treatment failure. Additionally, she suggested the following reasons for overdiagnosis of ADHD: SUD symptoms can mimic those of ADHD; diagnosis is based on screening or tests; and malingering. Finally, Dr Skoglund suggested that clinicians may have a reluctance to prescribe scheduled drugs to individuals with ADHD, as there is a risk they may be used non-medically, and individuals with comorbid SUD may be tolerant to stimulants.

Assessing and diagnosis ADHD in SUD

Dr Skoglund emphasised the importance of screening every individual with SUD for ADHD due to the high prevalence of ADHD in this population.55 Recommended screening scales include the Short Version of the Adult ADHD Self-Report Scale screener, the Conners’ Adult ADHD Rating Scale (CAARS), the Wender Utah Rating Scale or the Attention Deficit Scales for Adults.55 She suggested that there should be a team-based approach, including a psychiatrist and a psychologist, when assessing and diagnosing an individual with SUD and possible ADHD.55 Prior to assessments for ADHD, medical and psychiatric interviews should be completed, as well as differential diagnostics and urine toxicology.53,55-57 Additionally the Drug Abuse Screening Test and the Alcohol Use Disorders Identification Test should be performed both prior to and during assessment to monitor the individual’s substance use.55 During the assessment for ADHD, current symptoms should be noted, as well as collateral information and longitudinal history.53,55 She stated that focusing on alcohol- and drug-free periods can aid in untangling ADHD symptoms from symptoms of SUD.55

Dr Skoglund stated that assessment for ADHD can begin once drug and SUD history has been elucidated, during absences of clinical signs of intoxication or withdrawal, and when clinical history has been collected.55 Furthermore, she discussed how assessment and re-evaluation of preliminary diagnosis during treatment of SUD can aid in the diagnostic reliability and validity.55 Professor Skoglund opined that if clinical and longitudinal history and collection of collateral information is completed prior to completion of SUD treatment, ADHD assessment can start.

Treatment of ADHD and SUD

When treating individuals with ADHD and comorbid SUD, a multimodal (pharmacological treatment, psychoeducation and CBT) treatment approach should be adopted, which is tailored to each individual.55,58 She reiterated that pharmacological and cognitive support are important in treating individuals with SUD.55,58

Dr Skoglund’s key conclusions from her presentation included: comorbidity in ADHD is the rule, not the exception; comorbid ADHD and SUD increases the risk of lower retention to treatment and worse outcome; the most severe condition in individuals with comorbid ADHD and SUD should be treated first, although in some cases both disorders should be treated simultaneously; and early detection and intervention decreases the risk of negative outcomes and comorbidity.

Dr Skoglund: “Working with individuals ADHD and comorbid SUD is so rewarding”

Clinical Hot Topic 12: ADHD and substance-use disorders – clinical tips

The focus of Dr Lotta Borg Skoglund’s (Senior Consultant Psychiatrist, Uppsala University, Uppsala, Sweden) session was to discuss clinical tips for the assessment, diagnosis, treatment and management of individuals with ADHD and comorbid SUD. She stated that a review from Katzman et al provides directions about how to identify symptoms of comorbid psychiatric disorders in individuals with ADHD and how to manage them.59 In Dr Skoglund’s clinical experience, individuals with ADHD who are not diagnosed in childhood may experience low self-esteem as they enter adolescence, and may then experience negative interactions and develop psychiatric comorbidities.

Dr Skoglund explained how she assesses and diagnoses adults with ADHD and comorbid SUD using a team-based approach. This approach involves a psychiatrist and psychologist who are experienced in adult ADHD and addiction care.53,55 Prior to assessment of an individual, medical and psychiatric assessments and differential diagnostics should be performed in order to differentiate various somatic and psychiatric symptoms from one another to map out which symptoms are attributed to which disorder.53,55,56 Additionally, the Drug Abuse Screening Test and the Alcohol Use Disorders Identification Test can be used to assess and continuously follow the individual’s substance use.55,57 Urine toxicology can also be utilised, she suggested using it to monitor their substance use and to determine if they have relapsed.55 Dr Skoglund stated that family history of ADHD and SUD should also be investigated, as both disorders have a high degree of heritability.53 Finally, collateral information and longitudinal history should be recorded, as this can aid diagnosis of ADHD since symptoms are typically present during childhood and prior to SUD.53,55

Dr Skoglund suggested that the ideal situation for assessing and diagnosing ADHD in an individual with SUD would be in the absence of serious intoxication and with no serious withdrawal symptoms.55 However, this situation is not always possible; therefore, the drug and SUD history of the individual can be started earlier, as well as observation and screening for ADHD.55 Dr Skoglund suggested, based on her own clinical opinion, that being able to collect this information can motivate the individual to stop using substances and comply with clinical advice. She highlighted that during treatment for SUD, the individual should be continually assessed and re-evaluated to increase diagnostic validity and reliability.55

Dr Skoglund moved on to discuss treatment options for individuals with ADHD and SUD. She suggested that, wherever possible, long-acting stimulants should be prescribed rather than short-acting stimulants. Short-acting stimulants cause a larger change in extracellular dopamine levels, which could be perceived as a ‘high’ by individuals with SUD, and therefore could possibly be misused.60 Furthermore, clinicians should adopt a multimodal approach to treatment, which includes pharmacotherapy, psychoeducation and CBT or peer-support therapy to treat ADHD and comorbid SUD.55,58 Dr Skoglund conferred that clinicians may adopt an integrated ADHD and SUD treatment plan when targeting both disorders simultaneously.61,62 She suggested that the dose-response of individuals with ADHD and comorbid SUD who are prescribed stimulants should be monitored, as data suggest that this group may need different doses of stimulants in order to ensure an optimal response.63,64 Finally, Dr Skoglund reiterated how important it is to combine pharmacological and cognitive support for treatment of SUD.55

To conclude this session, Dr Skoglund provided some key points for the assessment and treatment of ADHD and SUD:

  • When ADHD is associated with a comorbidity, the more severe disorder should typically be treated first.53,65
  • Treatment for ADHD and psychiatric comorbidities should be integrated where appropriate.53,55
  • Typically, tolerance to stimulants is not shown in those with ADHD and SUD.66
  • Individuals with ADHD who receive treatment are more likely to not have SUD, and have good psychosocial functioning compared with those with ADHD who are untreated.67
  • Specialist advice should be sought where required, and clinicians should consider the most important need for each individual.
  • Non-treatment could deprive the individual of the chance to resolve any psychosocial, functional, personal, relationship or professional impairments.

Clinical Hot Topic 13: ADHD, depression and bipolar disorder

Professor Jan Haavik (Department of Biomedicine, University of Bergen, Bergen, Norway) began his presentation by defining comorbidity: “in a patient with a particular index disease, the term comorbidity refers to any additional coexisting ailment”.68 He opined that from a patient perspective, it is better to use ‘multimorbidity’ so that they understand there is more than one condition, but they do not need to know which is condition 1, 2 or 3. He clarified that ‘comorbid’ can also mean conditions existing simultaneously but independently, or related conditions.

ADHD, depression and bipolar disorder: diagnostic criteria

Professor Haavik next described the diagnostic criteria for ADHD according to the Diagnostic and Statistical Manual of Mental Disorders – 5th Edition (DSM-5TM).2 ADHD is diagnosed based on the presence of ≥6 symptoms of inattention and/or ≥6 symptoms of hyperactivity/impulsivity, which must be present in two or more settings before the age of 12 years and cause clear evidence of clinically significant impairment that cannot be better accounted for by another disorder.2 Professor Haavik suggested that there may be problems with diagnosing ADHD according to the criterion that ADHD symptoms should not be better accounted for by another mental disorder, as some psychiatric conditions can be comorbid. In addition to the core diagnostic criteria for ADHD, he added that there may be associated features supporting a diagnosis, such as low frustration tolerance, irritability or mood lability.2 He suggested that these associated features may be related to affective disorders, such as major depressive disorder and bipolar II disorder. The symptoms of ADHD were then listed, for example being easily distracted and forgetful, often ‘on the go’, talking excessively and having trouble waiting.2

Professor Haavik next described the diagnostic criteria for major depressive disorder.2 According to the DSM-5TM, major depressive disorder is described as having ≥5 depressive symptoms during the same 2-week period that are a change from previous functioning; ≥1 of the symptom(s) is either a depressed mood or loss of interest or pleasure.2 Professor Haavik highlighted that some symptoms of major depressive disorder appear to overlap with the diagnostic criteria for ADHD, including loss of interest, psychomotor agitation/restlessness and decreased concentration. Professor Haavik then summarised the diagnostic criteria for bipolar II disorder according to the DSM-5TM.2 He described how bipolar II disorder is diagnosed based on a hypomanic episode – which is different to a manic episode, which may lead to a diagnosis of bipolar I disorder. A hypomanic episode is a distinct period of abnormally and persistently elevated, expansive or irritable mood, and abnormally and persistently increased activity or energy, lasting ≥4 consecutive days. Again, Professor Haavik highlighted symptoms that appeared to overlap with ADHD, such as decreased need for sleep, talkativeness, flight of ideas/racing thoughts, distractibility, psychomotor agitation and involvement in activities with a high potential for painful consequences.2

Professor Haavik went on to briefly describe case histories of patients to put this information into context. In his clinical experience, he observed that mood or emotional instability is common in adult ADHD, whether it is part of the disorder, a comorbid condition or a ‘better explanation’ of the ADHD symptoms. He stated that it is important to consider ADHD in treatment-resistant depression. Professor Haavik then described some additional observations from his clinical cases, including that people with ADHD are at an increased risk of trauma, post-traumatic stress disorder and affective disorders, for which the interpretation of cause and effect may be difficult. Moreover, he noted that drug therapy alone is not usually enough for any psychiatric disorder, and that psychoeducation, dialectical behaviour therapy and skills training show promising results, and are important for compliance and long-term success in treating adult ADHD.

Professor Haavik then explained that the emotional instability and irritability in adult ADHD has been studied systematically, and research has found that the intensity and frequency of mood fluctuations are much stronger in people with ADHD than people without.69 He went on to introduce research comparing the classical diagnostic criteria for ADHD as reflected in the Adult ADHD Self-Report Scale (ASRS; which includes the 18-item ADHD symptoms checklist according to the DSM-5TM [or six items in a shorter screener]) with the Wender Utah Rating Scale (WURS; which includes 25 items chosen for discriminative ability). This study built on previous research in the 1970s that proposed the following symptoms for what is now known as ADHD: inattentiveness, hyperactivity, mood lability, irritability and hot temper, impaired tolerance, disorganisation and impulsivity.70 Professor Haavik described how, when these criteria were applied to a sample of adults with ADHD, it was found that the WURS was better than the ASRS and DSM-5TM criteria in discriminating between adults with ADHD and unaffected individuals.71 He concluded that this demonstrated that mood lability, irritability and hot temper, and impaired stress tolerance are quite frequent in adult ADHD, as the WURS criteria encompass this wider symptom range.

Evidence of comorbidity

Professor Haavik next described a study that investigated developmental trajectories of ADHD across the lifespan, including how the comorbidity profile in ADHD changes over time. This study described a theoretical trajectory in which the pattern of comorbidities was different in children versus adults. Comorbidities in children included ASDs, tics, learning disorders and rule-breaking behaviours, whereas in adolescents and adults, comorbidities included SUDs, mood and anxiety disorders, disruptive mood dysregulation disorder and bipolar disorder.72 Professor Haavik then described research into sex differences of psychiatric comorbidity in adult ADHD. This study found that ADHD cases had 4–9-times higher prevalence of anxiety, bipolar disorder, depression, personality disorder, schizophrenia and SUD than the remaining adult population. Furthermore, the differences in prevalence between adults with and without ADHD were significantly larger in women than men for all psychiatric disorders, except schizophrenia and SUD.73 Comparable studies in Sweden74 and Denmark75 found similar results of sex differences in comorbidities of ADHD. Genetic overlap of ADHD with other psychiatric disorders, including major depressive disorder and bipolar disorder, have also been shown in previous research.76 Furthermore, brain imaging studies have shown overlapping structural and genetic features of psychiatric disorders, which may explain high rates of comorbidity; for example, a correlation was observed between brain areas affected in ADHD and bipolar disorder.77

Treatment implications

Professor Haavik then referred to the NICE guidelines for the treatment of ADHD to highlight that any individual with ADHD experiencing an acute psychotic or manic episode is recommended to stop any medication and only consider restarting or starting new ADHD medication once the episode has resolved, taking into account the individual circumstances, risks and benefits of the ADHD medication.78 He suggested that in terms of treatment, the most severe condition should be treated first.

Professor Haavik concluded his presentation by summarising that ADHD, depression and bipolar disorder may have some overlapping symptoms, supported by epidemiological, genetic and structural imaging evidence. In his opinion, the main differences between ADHD and depression and bipolar disorder is that ADHD is more trait-like and has an earlier onset, while depression and bipolar disorder are more or less episodic. In his best judgement, treatment should always start with psychoeducation and by treating the most severe condition first, for example using a mood stabiliser for bipolar disorder first followed by stimulants for ADHD. Finally, he stressed that early intervention may prevent later complications.

Professor Haavik: “There might be certain cases where it’s difficult to make a decision whether its ADHD, depression or bipolar disorder”

Ask the Experts: Session 6 (discussion forum)

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

Panel: Professor Dan Stein (Professor & Chair of the Department of Psychiatry & Mental Health, University of Cape Town, Cape Town, South Africa); 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); Dr Lotta Borg Skoglund (Senior Consultant Psychiatrist, Uppsala University, Uppsala, Sweden).

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

‘How would you define neuroscience and where are we in the field now?’

Professor Nutt stated that it is the science of the neural system and the way that neurones work. He explained that although we are quite far in our journey of understanding, there is still plenty that we do now know, such as how many neurotransmitters there are. He stated that we have the capability to try and resolve this question in research. He explained that the focus is no longer clarifying the role of every gene in the brain, and is instead the diversity of neurotransmitters that give the brain its complexity and power. He added that there are not only >80 neurotransmitters to investigate but also approximately 15 subtypes of each receptor, such as the serotonin receptor for example. He added that the more recent capability for brain imaging studies, due to new technology, such as functional magnetic resonance imaging, has allowed us to observe the network function of the brain and its higher order networks. These networks orchestrate connections between the more primary networks (e.g. motor cortex, visual cortex) to give us our human abilities such as thinking, remembering and planning.

‘How do you define neuromythology and how is it different to the description of neuroscience?’

Professor Stein supposed that neuromythology was a matter of temperament and considered whether this description of the current status in the field of neuroscience is thought of as a major advance or whether the focus is instead on how little we currently know. He added that it is possible that from all of the brain imaging performed, it has highlighted how much we don’t know. He expanded on this point by highlighting that one of the issues is the low effect sizes. He explained that structural brain imaging across multiple disorders and multiple countries has demonstrated shared patterns of brain abnormalities across different disorders but with very small effect sizes. He indicated that this is reminiscent of the genetic evidence for psychiatric disorders. For example, no single disease-causing gene has been discovered for schizophrenia, and instead hundreds of possible genes (each with very small contributions) have been discovered. He summarised that this huge volume of complex data is hugely overwhelming.

‘Is there a genetic basis to addictive behaviour?’

Professor Nutt answered that genes and genetics are slightly different constructs. He continued that there is a definite genetic basis to addictive behaviour. He drew upon evidence from Danish studies which have shown that males of parents with alcohol problems had the same propensity for alcoholism when adopted into other families as when brought up by their own parents. These findings suggest that this addictive behaviour was inherited rather than learnt in the environment. He added that, in his opinion, it is evident that addictions to some drugs are largely genetic; heroin and cocaine both have a concordance in monozygotic twins of up to 70–80%, whereas drugs considered less addictive, such as psychedelic drugs, have lower concordances. From this, Professor Nutt summarised that there is some kind of inherited process that makes people vulnerable to drug dependency. He added that the underlying inherited processes or genes are currently unknown. Nevertheless, there is still a suggestion that addiction may be similar to schizophrenia, in the sense that different genetic factors underpin different propensities to addiction, such as impulsivity, craving and stress sensitivity.

Dr Skoglund added that it is easy to oversimplify the complex issue of addictive behaviour. She suggested that maybe the term ‘heritability’ is what is meant here. She added that large epidemiological studies suggest that there may be shared genetic factors between SUDs and ADHD. She emphasised that the most important message from the genetic evidence is to take away the shame and stigma around ADHD and SUDs.

Professor Stein interjected to ‘play devil’s advocate’ and suggested that almost anything is genetic – even things that we think of as environmental, such as socioeconomic status, may still have a heritable component. He added that one of the difficulties is that the exact heritability depends on the environment. Therefore, he explained that heritability percentages run the risk of genetic essentialism and ignore the fact that heritability relies on the environment. Building on this, Professor Stein explained that the effect sizes of polygenic risk cohorts are so small, it almost makes no difference. However, he also noted the potential impact of informing people they have a genetic problem, suggesting that this might reduce social stigma but it also might increase personal shame and embarrassment – possibly giving rise to the idea that “I come from a family who are genetically vulnerable, there is nothing I can do here”. He emphasised that careful phrasing is needed when informing people of their polygenic risk, including mentioning that they still have many life choices and an ability to override this risk.

Dr Skoglund agreed that this is extremely important, and patients should be informed that their polygenic risk is not deterministic.

Professor Nutt contributed that this idea is not controversial but he feels it is wise. In his opinion, genetics does not have as much value in the clinical setting yet, but is clearly a route to understanding what the biological vulnerabilities might be.

‘Is there such a thing as an addictive personality and, if so, is that what you see/are there characteristics that point to what people would describe as an addictive personality?’

Professor Nutt’s answer was no, people get addicted for a variety of reasons. For example, they have an underlying disorder that they are self-medicating, or they are dealing with stress, or perhaps they are young and being led astray by their peers. He stated that, in his opinion, there is not one single concept of addiction and that ‘addictive personality’ is a false construct.

‘Can you describe what happens in the brain with addictions, and what is occurring at the neurobiological level? In particular, is there a difference between behavioural addictions and chemical addictions?’

Professor Nutt replied that this is a great question and forms one of the reasons why his group study gambling. He explained that when changes in the neurotransmitters of the brain are observed in individuals with chemical addictions, it remains unknown if these are due to the drug or an underlying condition. Therefore, his group studies the behavioural addiction of gambling instead, so that any observed brain changes are known to be independent of drugs. Some of these observed changes include dopamine receptor changes, especially in the limbic system. Deficiencies in dopamine receptors have been observed in gamblers, particularly in those with high levels of urges, leading to the conclusion that dopamine in the limbic system has a restraining and stabilising influence on gambling behaviour. Professor Nutt further explained that this is what can be predicted from the value of increasing dopamine in people with ADHD, who share significant overlap with people with behaviour addictions in their inability to restrain urges. He highlighted research which found that the endogenous opioid system was deficient in gamblers. He added that this might be a predisposing factor to behavioural addictions, as people seek ways get a full release of endorphins.

Professor Stein referred back to the previous topic of genetics and brain imaging to add that he finds it useful to show individuals with obsessive compulsive disorder (OCD) brain images of OCD-related abnormalities as part of the psychoeducation process. He suggested it was beneficial to show these individuals that what they are experiencing is what he calls a ‘false alarm’. Using this technique, individuals with OCD can be aware of their actions and learn how they can change their behaviour to overcome any predisposing vulnerabilities.

Dr Skoglund agreed and added that this process is useful for people with ADHD too, even if the full picture of the predisposing vulnerabilities in this disorder is still unknown. She explained that the adolescents with ADHD she works with tend to prefer a more concrete approach to their problems such as this.

Professor Stein added that another way of thinking about addiction is via evolutionary aspects. He explained that in order to really understand biology, we have to understand how things evolve over time. He described how animal studies using paradigms of addictions, such as gambling, have shown that brain reward systems go awry in even our distant animal relatives. These findings suggest to him that evolutionary theory predicts that we all have a capacity to develop addictions.

‘Can you explore the relationship between impulsivity and compulsivity in behavioural addictions?’

Dr Skoglund described how, in her clinical practice, she finds it fascinating that impulsivity and compulsivity, as two extremes of a dimension, can be actively present in a single person. She expanded that it can be particularly confusing for the individual themselves, and so it is important to help them to understand the relationship between the two conditions. She added that both impulsivity and compulsivity should be factored in when assessing an individual.

Professor Nutt felt differently in that he sees them as completely independent constructs. He views compulsivity as when reward activity somehow gets moved from the ventral striatum to the caudate putamen (the habit system). Whereas, impulsivity is the failure of ventral control and the failure of the prefrontal cortex to regulate behaviour. He added that when he studies addiction he looks at both systems separately.

Dr Skoglund interjected that many of her patients tell her that their compulsivity is a defence against their impulsivity, with which Professor Nutt agreed.

Professor Stein added how he thinks reductionism of relationships between concepts such as these comes out of psychoanalytic theory. He expanded that a Freudian perspective would deem people as ‘only obsessed’ or ‘only neurotic,’ in that people can only be one thing or the other. He went on to describe the complexity of biological data and how a Freudian interpretation would be too reductionist. He moved on to explain that a less reductionist view would include that substance use begins with impulsivity and then becomes compulsivity. He agreed with Dr Skoglund that you tend to see both of these concepts in the clinic. For example, with gambling there is a great deal of repetitive habitual behaviour (compulsions) and also a lack of control in some ways (impulses).

‘What are the early signs for behavioural addiction?’

Professor Stein stated that we all understand we have temptations, but that if we sometimes give in to a temptation, it is not classed as an addiction. He expanded that, on the other hand, if a person continuously gives in to their temptations and does nothing else then that is when there is a problem.

Dr Skoglund added that it is helpful to look at the diagnostic reasoning around behavioural addiction, which in this case is about age appropriateness. She used an example of having a child who struggles to control themselves, and reasoning if this is in an age-appropriate way; for example, the difference between an 18-year-old versus a 6-year-old in struggling to control themselves. She added that other useful methods are to compare children in the classroom and to look at psychiatric disorders in the family and heritability. She emphasised that these signs should never be deterministic but a guide for open discussions with parents.

Professor Nutt expanded on this to say that high engagement in an activity is normal to a certain extent, even playing games. He gave an example of a tennis player who will devote themself to the game to make it to the top of their career but would not be considered an addict. He added that in some video games, the prize money offered can make gaming more of a career option rather than just a game. However, he stated that if children are reasoning their playing of video games to win prize money or develop a career then that is already a sign that it is not an addictive behaviour in their opinion, unless their school performance or performance in other activities becomes impaired, in which case that could be considered a ‘red flag’. He explained that this is comparable with all disorders in that it is the level of impairment that defines them.

Professor Stein said that when an individual starts betting on horse racing, for example, one way to prevent this may be to explain that the only person who makes money from betting is the bookmakers. He suggested that this approach could be used with children who play video games ‒ rather than playing for prize money or fame, realise that the person who made and owns the video game is really the one who always benefits from users playing the game.

‘How do you feel the COVID-19 pandemic has affected those with behavioural addictions? How have you adapted your practice to manage people with substance misuse and ADHD?’

Dr Skoglund summarised her recent findings that children and their families overall are struggling as a result of the COVID-19 pandemic. She explained that they are spending a lot less time on schoolwork and more time on other activities. From a clinical perspective, she noted that she is being presented with many individuals who can’t follow school or keep to a routine. She stated that although it is a huge challenge, there are also opportunities to discuss strategies to help them cope.

Professor Nutt added that it is inevitable that the COVID-19 pandemic will increase psychiatric problems, but his main worry is that there will be pressure to do everything online when people are suffering from a lack of social relationships. He emphasised that countries must form strategies to introduce social relationships once more.

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.

  • Dr Skoglund stated that clinicians should never use the presence of substance abuse or addiction as a means for not completing a full diagnostic assessment and treatment of ADHD.
  • Professor Stein chose to focus on a lesson from motivational interviewing and explained that using this technique, a clinician should not first state the harms of alcohol or gambling, and instead the clinician should begin by asking the individual, ‘tell me about the great things it brings to you’.
  • Professor Nutt said that the key thing is to instil hope; there are realistic opportunities to improve well-being and interactions with families.

Clinical Hot Topic 14: What do general adult psychiatrists really need to know about ADHD and mood disorders?

Professor Allan Young (Chair of Mood Disorders, King’s College London, London, UK) first discussed the overlapping symptoms between depression and ADHD. The overlapping symptoms between ADHD and major depressive disorder include restlessness, difficulty concentrating and decreased attention.79 Whereas, racing thoughts and impulsive behaviours are symptoms that overlap between ADHD and hypomanic bipolar disorder.79

Professor Young moved on to describe the shared genetic mechanisms and environmental risk factors which affect the structure and functional capacity of neural networks in the behaviour and cognition of individuals with ADHD.80 This is evidenced by a genome-wide association meta-analysis which provided data showing that the highest positive genetic correlation was between ADHD and major depressive disorder (p=7.38×10-38).81 There were also statistically significant positive genetics correlations between ADHD and depressive symptoms (p=7×10-19), and ADHD and neuroticism (p=1.02×10-8), and a negative correlation between ADHD and subjective well-being (p=3.73×10-9).81

Data were also presented which highlighted that individuals with ADHD have significantly higher all-cause mortality rates than those without ADHD (hazard ratio [HR] 1.42; 95% confidence interval [CI] 1.31‒1.54; p<0.001).82 The most probable causes of mortality for individuals with ADHD are suicide (HR, 3.19; 95% CI 2.56‒3.97; p<0.001), homicide (HR, 2.04; 95% CI 1.13–3.70; p=0.007) and unintentional injury (HR, 1.21; 95% CI 1.03–1.41; p=0.01).82 Furthermore, Professor Young stated that the greater the number of comorbidities an individual with ADHD has, the higher the mortality rate (ADHD only: HR, 1.56, 95% CI 1.11–2.18 compared with ADHD plus ≥4 comorbidities: HR, 29.29; 95% CI 22.77–37.66).83

Professor Young next highlighted a study of adults aged 18–65 years in psychiatric care, which estimated that 12.3% of 1215 individuals with depression also had ADHD.43 He noted that the ‘red flags’ of ADHD in adults can be broken down into three areas: individual, occupational and interpersonal. Symptoms of adult ADHD can then be observed through the various issues the individual is facing in each of the three core areas.65 He recommended the use of the ASRS v1.1 to aid in screening for ADHD in clinics.84 When evaluating an individual for ADHD, multiple stages of assessment occur prior to making a formal diagnosis.65,78,85,86 Assessments include: a clinical examination; clinical interviews with the individual and their partner/family; identification of the individual’s and family’s needs; and utilisation of assessment tools and rating scales.2,65,78,85,86 Professor Young also suggested the use of the Diagnostic Interview for ADHD in Adults to aid the diagnosis of adult ADHD.87

Professor Young opined that the benefits of treating an adult with ADHD can be seen in several areas such as increasing executive function and quality of life. Professor Young described the results of a systematic review of 48 studies and 76 outcome measures which highlighted the benefit of ADHD treatment in terms of improving driving ability in 100% of the outcome group compared with the untreated ADHD group.88 Additionally, 90% of the individuals with ADHD who were treated had an improvement in self-esteem, 83% of individuals had an improvement in social function and 67% of treated individuals with ADHD had an improvement in drug use and addiction.88 Furthermore, Professor Young highlighted results from a separate study, which evidenced the low numbers of children and adolescents (aged 6–17 years) with ADHD (out of the total sample with ADHD [n=265; boys n=130; girls n=135]), who needed to be treated with stimulants to prevent various negative lifetime outcomes.89

Professor Young stated that clinicians should take into consideration that the incidence of depression increases with age. A study highlighted that major depressive disorder occurs in 18.6% of adults with ADHD.44 He conferred that in the cases involving severe depression or suicide risk, the symptoms of depression should be treated first prior to treatment of ADHD. However, in mild cases, ADHD and depression can be treated concurrently as taking a stimulant and a serotonin uptake inhibitor is generally considered to be well tolerated.90

Finally, Professor Young provided prescribing recommendations for treating ADHD and anxiety. He stated that clinicians should be aware that anxiety exacerbates ADHD-related impairment, and the incidence of any anxiety disorder is 47% among adults with ADHD.44 He recommended that stimulants could be used in adults with ADHD and an anxiety disorder due to their effectiveness at treating ADHD symptoms which contribute to anxiety. Also, long-acting stimulants with smooth-release formulations are preferred over medications with distinct drug-release phases. Professor Young emphasised that medications should be titrated slowly and symptoms of anxiety can be monitored in conjunction with ADHD symptoms.90

Professor Young: “Treatment of adult ADHD … may lead to benefit … within a relatively short period of time”

Clinical Hot Topic 15: ADHD and medical comorbidities

Professor Luis Rohde (Professor of Child & Adolescent Psychiatry, Federal University of Rio Grande do Sul, Porto Alegre, Brazil) opened his session by reminding the audience that ADHD is a disorder highly comorbid with other psychiatric disorders, including mood disorders, learning disorders and SUDs.80 He stated that the National Comorbidity Survey Replication found 12-month prevalence rates in adult patients with ADHD to be 8% for generalised anxiety disorder and almost 20% for bipolar disorder.44 He went on to describe how ADHD can not only be comorbid with psychiatric disorders but also with neurological disorders. The Brainstorm Consortium found genetic correlations across neurological and psychiatric phenotypes, including ADHD and migraine.76 He emphasised the importance of not only looking for neurological and psychiatric comorbidities, but also medical comorbidities, as investigated using polygenic risk scores (PRS) in a study he described. This study found an increased PRS for medical comorbidities such as type II diabetes and childhood obesity.81

ADHD and obesity

Professor Rohde explained that associations have been found between ADHD and obesity. One study demonstrated significant associations between ADHD and obesity, independently of how obesity was defined.91 The significance was only lost when the definition of ADHD was limited to only those patients medicated, which Professor Rohde suggested made sense due to the effect of stimulants on decreasing appetite. This significant association was also shown using unadjusted odds ratios; however, Professor Rohde emphasised that these results do not show the direction of causality in the association. He next introduced the concept of Mendelian randomisation as a means to rule out reverse causation and uncover causality in associations, through using gene variants to interrogate cause and effect in epidemiological data.92 He described a study that used Mendelian randomisation to uncover the relationship between ADHD and obesity. This study found no consistent evidence to suggest that ADHD leads to obesity; however, there were significant associations to suggest that obesity leads to ADHD and not the other way round.93

ADHD and asthma

Professor Rohde then described how research has found a clear association between ADHD and asthma, in a combined meta-analysis and a Swedish population-based study and even when using unadjusted and adjusted odds ratios.94 However, Professor Rohde was quick to point out that this again only shows an association between ADHD and asthma and not the direction or causality. A Mendelian randomisation of genetic studies of ADHD and asthma showed a different relationship to what was discovered between ADHD and obesity; here, it appeared more likely that ADHD may increase the risk of asthma.95

ADHD and diabetes

Professor Rohde next introduced a meta-analysis that demonstrated an association between maternal diabetes and an increased risk of ADHD in offspring.96 To explain the association between type II diabetes, metabolic syndrome and ADHD, another study found common lifestyle factors among individuals with ADHD and individuals who are obese, for instance a sedentary lifestyle and abnormal eating patterns.97 Building on this, another study found a clear association between eating disorders and an increased risk of ADHD, upon which Professor Rohde commented that eating disorders may also be associated with diabetes so there may be common factors between ADHD and diabetes.98

How to explain ADHD comorbidity with medical disorders?

Professor Rohde next explained that one way to understand the prevalence of medical disorders as comorbidities of ADHD is through recent research into the gut microbiota as a recent review had shown potential associations of modifications in gut microbiota and ADHD.99 He expanded on this with evidence suggesting that modifications in the Western-type diet can result in modifications in the gut microbiota which are in turn associated with a cascade of modifications in inflammatory factors that activate the microglia and disrupt the blood–brain barrier. These modifications are also associated with type II diabetes, obesity and psychiatric disorders.100 Therefore, modifications in microbiota might be one way to explain the link between psychiatric and medical disorders. Professor Rohde explained how another way to explain this link is through the role of neuroinflammation. He described research that indicated that modifications in mast cells (involved in pathogenic brain inflammation in neuropsychiatric disorders) may cause or aggravate neuroinflammation through the release of inflammatory factors, which are in connection with glial cells and hypothalamic pituitary-adrenal axis activation or disruptions in the blood–brain barrier.101,102 He added that it is already known that there is a role played by inflammation in obesity, diabetes and asthma. Professor Rohde then described research that induced increases in in utero cytokines of pregnant rats via injected substances. It was found that this increased the inflammatory environment for the foetus and resulted in offspring which had clear alterations in brain regions related to ADHD, such as the dorsal lateral prefrontal cortex (PFC) area, the inferior PFC and the orbitofrontal cortex. Furthermore, modifications in neurotransmission (including for dopamine) were observed and these offspring had an ADHD-like phenotype: higher hyperactivity and impulsivity, lower attention and lower learning and memory.103 Professor Rohde surmised that neuroinflammation may be important to connect ADHD with medical comorbidities.

Why is it important to consider psychiatric comorbidities when dealing with individuals with ADHD?

Professor Rohde answered this question by presenting data from a study that documented a higher risk of mortality in individuals with ADHD. When the model was adjusted for other confounders this risk remained significant but did decrease. The risk of mortality in individuals with ADHD increased with increasing comorbidities.83 Therefore, Professor Rohde emphasised it is important to consider psychiatric comorbidities due to the impact on outcomes with ADHD.

Why is it important to consider medical comorbidities when dealing with individuals with ADHD?

Professor Rohde presented evidence from a study that assessed antecedents of ADHD, dementia and metabolic dysfunction. An unadjusted model found a significant association between having ADHD and developing Alzheimer’s disease later in life. When this model was adjusted for diabetes, the effect of ADHD on increased risk for dementia disappeared, suggesting it is carried by medical comorbidities.104

Professor Rohde summarised that ADHD is a highly comorbid disorder; however, the comorbidities are not only psychiatric disorders. Therefore, clinicians need to also pay attention to medical comorbidities such as asthma, obesity and diabetes. Although the pathophysiological mechanisms determining these comorbidities are not yet well understood, they might be related to modifications in the microbiome and/or immune or inflammatory processes. He emphasised that the presence of a medical comorbidity might negatively impact on the outcomes associated with ADHD.

Professor Rohde: “So there seems to exist a correlation not only between psychiatric disorders but also between ADHD and other medical disorders”

  1. Livingston LA, Happé F. Conceptualising compensation in neurodevelopmental disorders: reflections from autism spectrum disorder. Neurosci Biobehav Rev 2017; 80: 729-742.
  2. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. 2013.
  3. Thapar A, Cooper M. Attention deficit hyperactivity disorder. Lancet 2016; 387: 1240-1250.
  4. Kas MJ, Glennon JC, Buitelaar J, et al. Assessing behavioural and cognitive domains of autism spectrum disorders in rodents: current status and future perspectives. Psychopharmacology (Berl) 2014; 231: 1125-1146.
  5. Faraone SV, Rostain AL, Blader J, et al. Practitioner Review: Emotional dysregulation in attention-deficit/hyperactivity disorder – implications for clinical recognition and intervention. J Child Psychol Psychiatry 2019; 60: 133-150.
  6. Nijmeijer JS, Minderaa RB, Buitelaar JK, et al. Attention-deficit/hyperactivity disorder and social dysfunctioning. Clin Psychol Rev 2008; 28: 692-708.
  7. Goldstein S, Schwebach AJ. The comorbidity of pervasive developmental disorder and attention deficit hyperactivity disorder: results of a retrospective chart review. J Autism Dev Disord 2004; 34: 329-339.
  8. Mulligan A, Anney RJ, O’Regan M, et al. Autism symptoms in attention-deficit/hyperactivity disorder: a familial trait which correlates with conduct, oppositional defiant, language and motor disorders. J Autism Dev Disord 2009; 39: 197-209.
  9. Santosh PJ, Mijovic A. Social impairment in hyperkinetic disorder. Eur Child Adolesc Psychiatry 2004; 13: 141-150.
  10. van der Meer JM, Oerlemans AM, van Steijn DJ, et al. Are autism spectrum disorder and attention-deficit/hyperactivity disorder different manifestations of one overarching disorder? Cognitive and symptom evidence from a clinical and population-based sample. J Am Acad Child Adolesc Psychiatry 2012; 51: 1160-1172.e1163.
  11. Levy SE, Mandell DS, Schultz RT. Autism. Lancet 2009; 374: 1627-1638.
  12. Ramos-Quiroga JA, Nasillo V, Fernández-Aranda F, et al. Addressing the lack of studies in attention-deficit/hyperactivity disorder in adults. Expert Rev Neurother 2014; 14: 553-567.
  13. Harris MA, Brett CE, Johnson W, et al. Personality stability from age 14 to age 77 years. Psychol Aging 2016; 31: 862-874.
  14. Matthies S, van Elst LT, Feige B, et al. Severity of childhood attention-deficit hyperactivity disorder – a risk factor for personality disorders in adult life? J Pers Disord 2011; 25: 101-114.
  15. Jacob CP, Romanos J, Dempfle A, et al. Co-morbidity of adult attention-deficit/hyperactivity disorder with focus on personality traits and related disorders in a tertiary referral center. Eur Arch Psychiatry Clin Neurosci 2007; 257: 309-317.
  16. Philipsen A, Limberger MF, Lieb K, et al. Attention-deficit hyperactivity disorder as a potentially aggravating factor in borderline personality disorder. Br J Psychiatry 2008; 192: 118-123.
  17. Rösler M, Retz W, Yaqoobi K, et al. Attention deficit/hyperactivity disorder in female offenders: prevalence, psychiatric comorbidity and psychosocial implications. Eur Arch Psychiatry Clin Neurosci 2009; 259: 98-105.
  18. Lewinsohn PM, Rohde P, Seeley JR, et al. Axis II psychopathology as a function of Axis I disorders in childhood and adolescence. J Am Acad Child Adolesc Psychiatry 1997; 36: 1752-1759.
  19. Fischer M, Barkley RA, Smallish L, et al. Young adult follow-up of hyperactive children: self-reported psychiatric disorders, comorbidity, and the role of childhood conduct problems and teen CD. J Abnorm Child Psychol 2002; 30: 463-475.
  20. Biederman J, Petty CR, Monuteaux MC, et al. Adult psychiatric outcomes of girls with attention deficit hyperactivity disorder: 11-year follow-up in a longitudinal case-control study. Am J Psychiatry 2010; 167: 409-417.
  21. Hoogman M, Bralten J, Hibar DP, et al. Subcortical brain volume differences in participants with attention deficit hyperactivity disorder in children and adults: a cross-sectional mega-analysis. Lancet Psychiatry 2017; 4: 310-319.
  22. Vidal R, Valero S, Nogueira M, et al. Emotional lability: the discriminative value in the diagnosis of attention deficit/hyperactivity disorder in adults. Compr Psychiatry 2014; 55: 1712-1719.
  23. Ferrer M, Andión O, Matalí J, et al. Comorbid attention-deficit/hyperactivity disorder in borderline patients defines an impulsive subtype of borderline personality disorder. J Pers Disord 2010; 24: 812-822.
  24. Valero S, Ramos-Quiroga A, Gomà-i-Freixanet M, et al. Personality profile of adult ADHD: the alternative five factor model. Psychiatry Res 2012; 198: 130-134.
  25. Arteaga-Henríquez G, Rosales-Ortiz SK, Arias-Vásquez A, et al. Treating impulsivity with probiotics in adults (PROBIA): study protocol of a multicenter, double-blind, randomized, placebo-controlled trial. Trials 2020; 21: 161.
  26. Kessler RC, Hwang I, LaBrie R, et al. DSM-IV pathological gambling in the National Comorbidity Survey Replication. Psychol Med 2008; 38: 1351-1360.
  27. Pan YC, Chiu YC, Lin YH. Systematic review and meta-analysis of epidemiology of internet addiction. Neurosci Biobehav Rev 2020; 118: 612-622.
  28. Grubbs JB, Hoagland KC, Lee BN, et al. Sexual addiction 25 years on: a systematic and methodological review of empirical literature and an agenda for future research. Clin Psychol Rev 2020; 82: 101925.
  29. Stein DJ, Phillips KA, Bolton D, et al. What is a mental/psychiatric disorder? From DSM-IV to DSM-V. Psychol Med 2010; 40: 1759-1765.
  30. King DL, Chamberlain SR, Carragher N, et al. Screening and assessment tools for gaming disorder: a comprehensive systematic review. Clin Psychol Rev 2020; 77: 101831.
  31. Stein D, Chamberlain S, Fineberg N. An A-B-C model of habit disorders: hair-pulling, skin-picking, and other stereotypic conditions. CNS Spectr 2006; 11: 824-827.
  32. Pettorruso M, Zoratto F, Miuli A, et al. Exploring dopaminergic transmission in gambling addiction: a systematic translational review. Neurosci Biobehav Rev 2020; 119: 481-511.
  33. Sepede G, Tavino M, Santacroce R, et al. Functional magnetic resonance imaging of internet addiction in young adults. World J Radiol 2016; 8: 210-225.
  34. Argyriou E, Davison CB, Lee TTC. Response inhibition and internet gaming disorder: a meta-analysis. Addict Behav 2017; 71: 54-60.
  35. Cowlishaw S, Merkouris S, Dowling N, et al. Psychological therapies for pathological and problem gambling. Cochrane Database Syst Rev 2012; 11: Cd008937.
  36. Gooding P, Tarrier N. A systematic review and meta-analysis of cognitive-behavioural interventions to reduce problem gambling: hedging our bets? Behav Res Ther 2009; 47: 592-607.
  37. Peter SC, Brett EI, Suda MT, et al. A meta-analysis of brief personalized feedback interventions for problematic gambling. J Gambl Stud 2019; 35: 447-464.
  38. Zajac K, Ginley MK, Chang R, et al. Treatments for internet gaming disorder and internet addiction: a systematic review. Psychol Addict Behav 2017; 31: 979-994.
  39. Liu S, Xiao T, Yang L, et al. Exercise as an alternative approach for treating smartphone addiction: a systematic review and meta-analysis of random controlled trials. Int J Environ Res Public Health 2019; 16: 3912.
  40. Goslar M, Leibetseder M, Muench HM, et al. Pharmacological treatments for disordered gambling: a meta-analysis. J Gambl Stud 2019; 35: 415-445.
  41. Stein DJ, Billieux J, Bowden-Jones H, et al. Balancing validity, utility and public health considerations in disorders due to addictive behaviours. World Psychiatry 2018; 17: 363-364.
  42. Fayyad J, Sampson NA, Hwang I, et al. The descriptive epidemiology of DSM-IV Adult ADHD in the World Health Organization World Mental Health Surveys. Atten Defic Hyperact Disord 2017; 9: 47-65.
  43. Deberdt W, Thome J, Lebrec J, et al. Prevalence of ADHD in nonpsychotic adult psychiatric care (ADPSYC): a multinational cross-sectional study in Europe. BMC Psychiatry 2015; 15: 242.
  44. Kessler RC, Adler L, Barkley R, et al. The prevalence and correlates of adult ADHD in the United States: results from the National Comorbidity Survey Replication. Am J Psychiatry 2006; 163: 716-723.
  45. Barkley RA, Fischer M, Smallish L, et al. Young adult follow-up of hyperactive children: antisocial activities and drug use. J Child Psychol Psychiatry 2004; 45: 195-211.
  46. Armstrong TD, Costello EJ. Community studies on adolescent substance use, abuse, or dependence and psychiatric comorbidity. J Consult Clin Psychol 2002; 70: 1224-1239.
  47. Hodgins S, Tengström A, Bylin S, et al. Consulting for substance abuse: mental disorders among adolescents and their parents. Nord J Psychiatry 2007; 61: 379-386.
  48. Banerjee TD, Middleton F, Faraone SV. Environmental risk factors for attention-deficit hyperactivity disorder. Acta Paediatr 2007; 96: 1269-1274.
  49. Thapar A, Cooper M, Jefferies R, et al. What causes attention deficit hyperactivity disorder? Arch Dis Child 2011; 97: 260-265.
  50. Larsson H, Anckarsater H, Råstam M, et al. Childhood attention-deficit hyperactivity disorder as an extreme of a continuous trait: a quantitative genetic study of 8,500 twin pairs. J Child Psychol Psychiatry 2012; 53: 73-80.
  51. Skoglund C, Chen Q, D’Onofrio BM, et al. Familial confounding of the association between maternal smoking during pregnancy and ADHD in offspring. J Child Psychol Psychiatry 2014; 55: 61-68.
  52. Skoglund C, Chen Q, Franck J, et al. Attention-deficit/hyperactivity disorder and risk for substance use disorders in relatives. Biol Psychiatry 2015; 77: 880-886.
  53. Kooij SJJ, Bejerot S, Blackwell A, et al. European Consensus Statement on diagnosis and treatment of adult ADHD: The European Network Adult ADHD. BMC Psychiatry 2010; 10: 67.
  54. Weiss MD, Weiss JR. A guide to the treatment of adults with ADHD. J Clin Psychiatry 2004; 65 Suppl 3: 27-37.
  55. Crunelle CL, van den Brink W, Moggi F, et al. International Consensus Statement on screening, diagnosis and treatment of substance use disorder patients with comorbid attention deficit/hyperactivity disorder. Eur Addict Res 2018; 24: 43-51.
  56. Martinez-Raga J, Knecht C, Szerman N, et al. Risk of serious cardiovascular problems with medications for attention-deficit hyperactivity disorder. CNS Drugs 2013; 27: 15-30.
  57. McCann BS, Simpson TL, Ries R, et al. Reliability and validity of screening instruments for drug and alcohol abuse in adults seeking evaluation for attention-deficit/hyperactivity disorder. Am J Addict 2000; 9: 1-9.
  58. Goossensen MA, van de Glind G, Carpentier P-J, et al. An intervention program for ADHD in patients with substance use disorders: preliminary results of a field trial. J Subst Abuse Treat 2006; 30: 253-259.
  59. Katzman MA, Bilkey TS, Chokka PR, et al. Adult ADHD and comorbid disorders: clinical implications of a dimensional approach. BMC Psychiatry 2017; 17: 302.
  60. Volkow ND, Swanson JM. Variables that affect the clinical use and abuse of methylphenidate in the treatment of ADHD. Am J Psychiatry 2003; 160: 1909-1918.
  61. Zulauf CA, Sprich SE, Safren SA, et al. The complicated relationship between attention deficit/hyperactivity disorder and substance use disorders. Curr Psychiatry Rep 2014; 16: 436.
  62. Torrens M, Rossi PC, Martinez-Riera R, et al. Psychiatric co-morbidity and substance use disorders: treatment in parallel systems or in one integrated system? Subst Use Misuse 2012; 47: 1005-1014.
  63. Konstenius M, Jayaram-Lindström N, Guterstam J, et al. Methylphenidate for attention deficit hyperactivity disorder and drug relapse in criminal offenders with substance dependence: a 24-week randomized placebo-controlled trial. Addiction 2014; 109: 440-449.
  64. Levin FR, Mariani JJ, Specker S, et al. Extended-release mixed amphetamine salts vs placebo for comorbid adult attention-deficit/hyperactivity disorder and cocaine use disorder: a randomized clinical trial. JAMA Psychiatry 2015; 72: 593-602.
  65. Canadian ADHD Resource Alliance (CADDRA). Canadian ADHD Practice Guidelines. Edition 4.1. Toronto, ON: CADDRA, 2020.
  66. Skoglund C, Brandt L, D’Onofrio B, et al. Methylphenidate doses in attention deficit/hyperactivity disorder and comorbid substance use disorders. Eur Neuropsychopharmacol 2017; 27: 1144-1152.
  67. Bihlar Muld B, Jokinen J, Bölte S, et al. Long-term outcomes of pharmacologically treated versus non-treated adults with ADHD and substance use disorder: a naturalistic study. J Subst Abuse Treat 2015; 51: 82-90.
  68. Feinstein AR. The pre-therapeutic classification of co-morbidity in chronic disease. J Chronic Dis 1970; 23: 455-468.
  69. Skirrow C, Ebner-Priemer U, Reinhard I, et al. Everyday emotional experience of adults with attention deficit hyperactivity disorder: evidence for reactive and endogenous emotional lability. Psychol Med 2014; 44: 3571-3583.
  70. Wood DR, Reimherr FW, Wender PH, et al. Diagnosis and treatment of minimal brain dysfunction in adults: a preliminary report. Arch Gen Psychiatry 1976; 33: 1453-1460.
  71. Brevik EJ, Lundervold AJ, Haavik J, et al. Validity and accuracy of the Adult Attention-Deficit/Hyperactivity Disorder (ADHD) Self-Report Scale (ASRS) and the Wender Utah Rating Scale (WURS) symptom checklists in discriminating between adults with and without ADHD. Brain Behav 2020; 10: e01605.
  72. Franke B, Michelini G, Asherson P, et al. Live fast, die young? A review on the developmental trajectories of ADHD across the lifespan. Eur Neuropsychopharmacol 2018; 28: 1059-1088.
  73. Solberg BS, Halmøy A, Engeland A, et al. Gender differences in psychiatric comorbidity: a population-based study of 40 000 adults with attention deficit hyperactivity disorder. Acta Psychiatr Scand 2018; 137: 176-186.
  74. Chen Q, Hartman CA, Haavik J, et al. Common psychiatric and metabolic comorbidity of adult attention-deficit/hyperactivity disorder: a population-based cross-sectional study. PLoS One 2018; 13: e0204516.
  75. Ottosen C, Larsen JT, Faraone SV, et al. Sex differences in comorbidity patterns of attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry 2019; 58: 412-422.e413.
  76. Anttila V, Bulik-Sullivan B, Finucane HK, et al. Analysis of shared heritability in common disorders of the brain. Science 2018; 360: eaap8757.
  77. Opel N, Goltermann J, Hermesdorf M, et al. Cross-disorder analysis of brain structural abnormalities in six major psychiatric disorders: a secondary analysis of mega- and meta-analytical findings from the ENIGMA consortium. Biol Psychiatry 2020; 88: 678-686.
  78. NICE guideline 2018. Attention deficit hyperactivity disorder: diagnosis and management. Available at: Accessed November 2020.
  79. Kooij JJ, Huss M, Asherson P, et al. Distinguishing comorbidity and successful management of adult ADHD. J Atten Disord 2012; 16(5 Suppl): 3S-19S.
  80. Faraone SV, Asherson P, Banaschewski T, et al. Attention-deficit/hyperactivity disorder. Nat Rev Dis Primers 2015; 1: 15020.
  81. Demontis D, Walters RK, Martin J, et al. Discovery of the first genome-wide significant risk loci for attention deficit/hyperactivity disorder. Nat Genet 2019; 51: 63-75.
  82. Chen VC-H, Chan H-L, Wu S-I, et al. Attention-deficit/hyperactivity disorder and mortality risk in Taiwan. JAMA Netw Open 2019; 2: e198714-e198714.
  83. Sun S, Kuja-Halkola R, Faraone SV, et al. Association of psychiatric comorbidity with the risk of premature death among children and adults with attention-deficit/hyperactivity disorder. JAMA Psychiatry 2019; 76: 1141-1149.
  84. World Health Organization. Adult ADHD Self-Report Scale-V1.1 (ASRS-V1.1) symptoms checklist. Available at: Accessed November 2020.
  85. 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.
  86. Kooij JJS, Bijlenga D, Salerno L, et al. Updated European Consensus Statement on diagnosis and treatment of adult ADHD. Eur Psychiatry 2019; 56: 14-34.
  87. Kooij JJS, Francken MH. Diagnostic Interview for ADHD in Adults (DIVA). 2010. Available at: Accessed November 2020.
  88. Shaw M, Hodgkins P, Caci H, et al. A systematic review and analysis of long-term outcomes in attention deficit hyperactivity disorder: effects of treatment and non-treatment. BMC Med 2012; 10: 99.
  89. Biederman J, DiSalvo M, Fried R, et al. Quantifying the protective effects of stimulants on functional outcomes in attention-deficit/hyperactivity disorder: a focus on number needed to treat statistic and sex effects. J Adolesc Health 2019; 65: 784-789.
  90. Mattingly GW, Wilson J, Ugarte L, et al. Individualization of attention-deficit/hyperactivity disorder treatment: pharmacotherapy considerations by age and co-occurring conditions. CNS Spectr 2020: 1-20.
  91. Cortese S, Moreira-Maia CR, St Fleur D, et al. Association between ADHD and obesity: a systematic review and meta-analysis. Am J Psychiatry 2016; 173: 34-43.
  92. Adam D. The gene-based hack that is revolutionizing epidemiology. Nature 2019; 576: 196-199.
  93. Martins-Silva T, Vaz JDS, Hutz MH, et al. Assessing causality in the association between attention-deficit/hyperactivity disorder and obesity: a Mendelian randomization study. Int J Obes (Lond) 2019; 43: 2500-2508.
  94. Cortese S, Sun S, Zhang J, et al. Association between attention deficit hyperactivity disorder and asthma: a systematic review and meta-analysis and a Swedish population-based study. Lancet Psychiatry 2018; 5: 717-726.
  95. Zhu Z, Zhu X, Liu CL, et al. Shared genetics of asthma and mental health disorders: a large-scale genome-wide cross-trait analysis. Eur Respir J 2019; 54.
  96. Guo D, Ju R, Zhou Q, et al. Association of maternal diabetes with attention deficit/hyperactivity disorder (ADHD) in offspring: a meta-analysis and review. Diabetes Res Clin Pract 2020; 165: 108269.
  97. Landau Z, Pinhas-Hamiel O. Attention deficit/hyperactivity, the metabolic syndrome, and type 2 diabetes. Curr Diab Rep 2019; 19: 46.
  98. Nazar BP, Bernardes C, Peachey G, et al. The risk of eating disorders comorbid with attention-deficit/hyperactivity disorder: a systematic review and meta-analysis. Int J Eat Disord 2016; 49: 1045-1057.
  99. Bundgaard-Nielsen C, Knudsen J, Leutscher PDC, et al. Gut microbiota profiles of autism spectrum disorder and attention deficit/hyperactivity disorder: a systematic literature review. Gut Microbes 2020; 11: 1172-1187.
  100. Slyepchenko A, Maes M, Jacka FN, et al. Gut microbiota, bacterial translocation, and interactions with diet: pathophysiological links between major depressive disorder and non-communicable medical comorbidities. Psychother Psychosom 2017; 86: 31-46.
  101. Leffa DT, Torres ILS, Rohde LA. A review on the role of inflammation in attention-deficit/hyperactivity disorder. Neuroimmunomodulation 2018; 25: 328-333.
  102. Song Y, Lu M, Yuan H, et al. Mast cell-mediated neuroinflammation may have a role in attention deficit hyperactivity disorder (Review). Exp Ther Med 2020; 20: 714-726.
  103. Dunn GA, Nigg JT, Sullivan EL. Neuroinflammation as a risk factor for attention deficit hyperactivity disorder. Pharmacol Biochem Behav 2019; 182: 22-34.
  104. Fluegge K, Fluegge K. Antecedent ADHD, dementia, and metabolic dysregulation: a U.S. based cohort analysis. Neurochem Int 2018; 112: 255-258.