The 8th World Congress on ADHD (2021) - Post-Conference Wrap Up - Doctor Unite

 
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The 8th World Congress on ADHD (2021) - Post-Conference Wrap Up - Doctor Unite
The    8
      World Congress
         th

on ADHD (2021)
Post-Conference Wrap Up
The 8th World Congress on ADHD (2021) - Post-Conference Wrap Up - Doctor Unite
2021 ADHD World Congress
   Post-Conference Wrap Up

                               2021 ADHD World Congress Wrap Up

   The 2021 ADHD World Congress was held virtually on May 6th-May 9th,
   due to the COVID-19 pandemic. Numerous updates were presented on
   current research within ADHD, and we summarize some additional
   exciting topics from the meeting including hot topics in ADHD
   epidemiology.

   Plenary: Update on treatment of ADHD over the lifespan
   001 –Advances in non-pharmacological treatments (food and nutrition-
   based interventions etc.)
   • Research paper: Bosch, Annick, et al. "A two arm randomized
      controlled trial comparing the short and long term effects of an
      elimination diet and a healthy diet in children with ADHD (TRACE
      study). Rationale, study design and methods." BMC psychiatry 20
      (2020): 1-16.
   •     Dr Jan K. Buitelaar (Radboud University Nijmegen, Donders Institute
         for Brain, Cognition, and Behavior) summarized diet and nutrition
         approaches to ADHD treatment. Nutritional psychiatry examines the
         relationship between diet and neurobiology and this is a more recent
         topic of clinical and research interest. Novel non-pharmacological
         advances in nutritional psychiatry are necessary as existing treatments
         are limited to short-term efficacy and do not have convincingly
         established long-term benefits. Furthermore, additional benefits are
         needed beyond symptom reduction including improving quality of life
         and more benign side effect profiles. Food interventions have been
         investigated two types of studies in ADHD: supplementation and
         elimination studies. Dr Buitelaar presented on the supplementation of
         omega-3 fatty acids and micro-nutrients as well as the elimination of
         artificial food colors and preservatives, sucrose, and a rigorously
         restrictive elimination diet.
   •     Omega-3 levels are reduced in children with ADHD and there is
         sufficient evidence to consider omega-3 fatty acids to supplement
         established therapies, however it is unclear whether this should be
         limited to children with low blood levels. Omega-3 fatty acids are a
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The 8th World Congress on ADHD (2021) - Post-Conference Wrap Up - Doctor Unite
2021 ADHD World Congress
   Post-Conference Wrap Up

   main constituent of the brain and cannot be synthesized in the body,
   thus are essential in external nutrition. A meta-analysis (Bloch et al.,
   2012) of 9 studies (n=586) highlighted a 0.42 effect size (p
The 8th World Congress on ADHD (2021) - Post-Conference Wrap Up - Doctor Unite
2021 ADHD World Congress
   Post-Conference Wrap Up

        0.46 to 0.67. A double-blind randomized, controlled trial in ADHD
        patients aged 7-12 years old (Rucklidge et al., 2018), demonstrated
        clinically meaningful improvement on inattentive symptoms (32%
        versus 9%) but no difference in hyperactive-impulsive symptoms.
   •    Artificial food colors and preservatives may be eliminated as add-on
        on treatment for some ADHD cases as it has a small effect size. A
        meta-analysis of 20 studies (794 participants) by Nigg et al. found a
        small parent-reported effect size of 0.18, while the teacher/observer
        effect size was non-significant. In contrast, Sonuga-Barke et al.
        highlighted a greater effect size with teacher ratings (0.42) versus
        parent ratings (0.32).
   •    Eliminating sucrose only affords a small effect size and is not qualified
        as a stand-alone treatment. Observational studies evaluated in a
        meta-analysis by Farsad-Naemi (2020) show a positive relationship
        between sugar and symptoms of ADHD. However, additional studies
        are required to examine the long-term effects of high sugar intake.
   •     Children with ADHD have an increased risk of developing adverse
         physical reactions to allergenic foods (De Theije et al., 2014). It may be
         that adverse physical reactions to food have an impact on the brain
         via the microbiome causing adverse behavioral affects. The
         elimination diet removing these foods is the most stringent nutritional
         approach and long-term effects are unknown. A meta-analysis by
         Sonuga-Barke et al. (2013) elicited a 1.48 effect size (p=0.01),
         conversely, when a study was taken out due to variability, the effect
         size was no longer statistically significant. The elimination diet may be
         difficult to implement and research by Pelsser (2020) reported that
         only 26% of participants in the intent-to-treat cohort maintained the
         diet. The TRACE randomized controlled trial comparing short and
         long-term effects of an elimination diet versus a healthy diet in
         children with ADHD is ongoing (Bosch et al., 2020).

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The 8th World Congress on ADHD (2021) - Post-Conference Wrap Up - Doctor Unite
2021 ADHD World Congress
   Post-Conference Wrap Up

   Plenary: Update on the ADHD aetiology and neurobiology
   004 –Progress in the genetics and epigenetics research in ADHD
   •     Dr. Barbara Franke (Radboud University, Netherlands) presented on
         the current progress that has been made on the genetics and
         epigenetics research within the ADHD field. Currently it is known that
         ADHD has high heritability with estimates reaching 74% from studies
         in twin siblings (Faraone and Larsson, Mol Psychiatry, 2019). While
         there is no one gene that contributes to ADHD, it is known that ADHD
         is a complex multifactorial disorder with multiple genes and
         environmental factors involved.
   •     In 2007 the Psychatric Genomics Consortium (PGC) was started in
         order to bring together scientists and genomic data on psychiatric
         disorders which successfully published a seminal paper in
         schizophrenia in 2014. Within ADHD, additional samples were needed
         bringing data from both PGC and another consortium, iPsych, which
         resulted in 12 genome-wide significant findings associated with ADHD
         from over 20,000 ADHD cases and over 35,000 control samples
         (Demontis, Walters, et al., Nature Genetics 2019). Further, it has been
         found that the 12 gene products interact in pathways that involve
         neurite outgrowth, synapse formation, and synaptic plasticity
         (Klemann, Poelmans, et al., in preparation; Poelmans et al., Am J
         Psychiatry 2011).
   •     Since ADHD persistence fluctuates by age, a Genome-wide association
         study (GWAS) was utilized to compare childhood ADHD and adult
         ADHD. Genetic correlations or the overlap between children and
         adults was high but there were also some differences found which
         agrees with prior research that found only part of those genes
         contributing to ADHD onset also play a role in ADHD persistence
         (Rovira et al., Neuropsychopharmacology 2020).
   •     In terms of genetic overlap between ADHD and other psychiatric
         comorbidities, it was found that ADHD has significant overlap with
         diseases such as anorexia, ASD, bipolar, depression, schizophrenia,
         and Tourette syndrome (see next page):

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2021 ADHD World Congress
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         •     Interestingly, genetic overlap of ADHD occurs as well with many non-
               psychiatric diseases:

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   •     Dr. Franke’s group used this data to look at the genetic sharing of
         ADHD and BMI/obesity and identified genome-wide significant ADHD-
         BMI and ADHD-obesity genes that increased significance by at least
         one order of magnitude, and then performed biological pathway
         enrichment analyses. One of the main contributors to the overlap
         between the ADHD and BMI/obesity comorbidity is dopamine
         signaling (Mota et al., Neuropsychopharmacology, 2020). Interestingly,
         this finding is consistent with the reversal of risk increase for obesity
         in ADHD upon treatment with stimulants (Cortese et al., Am J
         Psychiatry, 2016).
   •     Like the GWAS, arrays have been used for epigenome-wide
         association-studies (EWAS) looking at altered DNA-methylation
         patterns in ADHD. A meta-analysis performed in Dr. Franke’s group
         found that the enriched cellular processes are those involved with
         developmental growth, axon guidance, and positive regulation of
         neuron differentiation, and the enriched cellular components included
         those associated with nucleoplasm, focal adhesion, dendritic spine,
         and synapse. Out of these studies, the top brain cell type marker for
         these ADHD-specific enrichments are in neurons which were similar to
         findings in the GWAS studies. Interestingly, only 1% of the top
         epigenetic findings for ADHD were directly explained by genetic
         factors involved in ADHD suggesting an important role for epigenetics
         as well as genetic studies in ADHD.
   •     The study of ADHD genetics and epigenetics is largely undeveloped
         and additional future studies need to be done for the development of
         diagnostic biomarkers and treatment targets for ADHD, prognostic
         biomarkers, personalized therapies, and a rethinking of psychiatric
         nosology.

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   Posters: Pharmacological treatment, children and adolescents
   Efficacy and Safety of KP415 (Serdexmethylphenidate and d-
   methylphenidate) Capsules in Children with ADHD: A randomized,
   double-blind, placebo-controlled laboratory classroom study
   • KP415 (Azstarys) is a recently approved once-daily capsule product for
       ADHD containing 70% serdexmethylphenidate (SDX) (a novel prodrug
       of d-methylphenidate) and 30% d-methylphenidate hydrochloride (d-
       MPH HCl). This randomized, double-blind, placebo-controlled
       laboratory classroom study demonstrated the favorable efficacy and
       safety of KP415 in children with ADHD who were aged 6-12 years.
   • After the screening phase, the study included a 3-week open-label
       dose optimization phase followed by a 1-week double-blind treatment
       phase testing 74 patients in the KP415 group and 76 in the control
       group. The following SDX/d-MPH dosage strengths were investigated:
       26.1/5.2mg (equivalent to 20mg d-MPH HCl), 39.2/7.8mg (equivalent
       to 30mg d-MPH HCl), and 52.3/10.4mg (equivalent to 40mg d-MPH
       HCl).
   • Statistically significant results were achieved on the pre-specified
       primary endpoint with a least-squares (LS) mean change over placebo
       of -5.41 in Swanson, Kotkin, Agler, M-Flynn, and Pelham-C (SKAMP-C)
       scores collected at the end of the dose optimization period (visit 5)
       compared to the end of the treatment period (visit 6) at day 28
       (p
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        was not met at the beginning (30 minutes) and end (12-13 hours)
        when assessing SKAMP-C with visit 5 as the baseline.

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   •     KP415 was generally well-tolerated and reported adverse events were
         typical of stimulant treatment. 31.1% of KP415 patients reported any
         treatment-emergent adverse events (TEAEs) compared to 14.5% of
         the placebo cohort. No serious adverse events were reported,
         however the most commonly reported TEAEs included upper
         respiratory tract infection (2.7% versus 5.3%), headache (5.4% versus
         1.3%), upper abdominal pain (4.1% versus 1.3%), insomnia (2.7%
         versus 1.3%), and pharyngitis (2.7% versus 0%). 4 subjects
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       experienced adverse events leading to treatment discontinuation
       and 2 of these cases reported severe insomnia.
   A post hoc analysis of executive function outcome of SPN-812
   (viloxazine extended-release) capsules in children and adolescents with
   ADHD
   • Vilazodone extended-release (ER) (Qelbree) is a recently approved
       once-daily capsule nonstimulant for the treatment of ADHD in
       pediatric patients 6-17 years of age. The drug was studied in 4 Phase
       III clinical trials in children and adolescents and this post-hoc analysis
       highlighted the positive effect of viloxazine ER on executive function
       deficits (EFDs) in the pooled data for 1154 subjects (viloxazine n=760,
       placebo n=394) from these studies.
   • Responders were defined as:
       •    >70 T-score at baseline (defined as severe impairment as this falls
            above 2 standard deviations of the population mean) and
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   •     Viloxazine ER improved executive function (EF) and ADHD symptoms.
         There were 52.5% of C3PS-EF or ADHD-RS-5 responders in the
         viloxazine ER treatment group versus 35.4% in the placebo group
         (p70 was 0.12
         and a comparable difference of 0.11 was yielded for all subjects.
   •     Among the patients receiving viloxazine ER, the correlation between
         the magnitude of EFD response and ADHD symptom response was r =
         0.47 (p
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   Hot Topic: Diet and ADHD: an epidemiological perspective

   001 - Moderating effect of maternal nutrition during pregnancy on the
   genetics of ADHD symptoms in children. A longitudinal study in the
   Norwegian Mother, Father and Child cohort
   • Dr. Berit Skretting Solberg presented the results of a study which
      aimed to examine the effects of prenatal maternal fiber intake (as a
      proxy of overall diet quality) and common genetic variants (calculated
      ADHD polygenic risk scores) on the development of ADHD in offspring
      at 3, 5, and 8 years of age (levels of symptoms measured and given
      ADHD scores).
   • The Norweigen Mother, Father and Child Cohort (MoBa) was
      examined in this study, which included ~95,000 mothers, ~75,000
      fathers and ~114,000 children who underwent questionnaires and
      DNA sampling between 1999-2008. The final study sample included
      father, mother, child trios at 3 years (n= ~6,000), 5 years (n=~5,000),
      and 8 years (n=~4,500).
   • The study concluded that there is a correlation between maternal
      fiber intake during pregnancy and ADHD symptoms in offspring, but
      the association was very weak. The study also found genetic effects of
      common variants were associated with ADHD score at 5 and 8 years of
      age, and offspring polygenic risk score showed positive correlation
      with change in ADHD scores over the study period. The results must
      be interpreted carefully as the sample size was small and a larger
      study sample is required to adjust the analysis for confounders.

   002 - ADHD symptoms and dietary habits in adulthood: a large
   population-based twin study in Sweden
   • Lin Li presented details of a study conducted to assess the association
      of ADHD in adulthood and dietary habits. The analysis particularly
      aimed to understand whether the symptomatic dimensions of ADHD
      (such as inattention, hyperactivity, and impulsivity) are specifically
      associated with certain dietary habits.
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   •     The data source used was the Study of Twin Adults: Genes and
         Environment (STAGE), which comprised of adult twins aged 20-47
         years old whom completed a food frequency questionnaire and were
         assessed for ADHD symptom scores (N=17,999). In this study, ADHD
         trait dimensions were positively associated with unhealthy dietary
         habits, and negatively associated with healthy dietary habits. The
         correlation of inattention and dietary habits was stronger than the
         correlation between hyperactivity/impulsivity and diet. But, future
         longitudinal studies with varying study designs are required to confirm
         any associations.
    003 - Impulsivity is associated with food intake, snacking, eating
   disorders and obesity in a general population
   • Sandrine Peneau presents results from the NutriNet-Sante cohort
      study investigating the effect of impulsive behaviour traits (measured
      using the Barratt Impulsiveness Scale, BIS-11), which are common in
      ADHD, and unhealthy dietary behaviour. The cohort consisted of
      51,368 adult participants in a web-based questionnaire which asks
      specific questions about their behaviour and food intake.
   • The results of this study suggest impulsive behaviour correlates with
      poorer diet quality, increased snacking, presence of eating disorders
      and being overweight or obese. Further longitudinal and experimental
      studies are required to understand and confirm these correlations.

   004 - Diet, physical activity and behavioral disinhibition in middle-aged
   and older adults: a UK Biobank study
   • Dr. Lizanne Schweren, PhD presents results from an analysis of the UK
      biobank cohort (N=150,000) of middle-aged and older adults (aged
      40-69 years), which aimed to answer the following research
      questions:
                     1. Is ADHD associated with poor diet among middle-aged and
                     older adults?
                     2. Which dietary features are associated with ADHD?
                     3. Are these associations age- and/or sex-specific?

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   •     Participants of UK biobank cohort undergo multiple questionnaires
         and multiple metrics are available including self-reported diagnoses of
         mental illness (including ADHD), personality traits (e.g. behavioural
         disinhibition), substance use, and ICD-10 hospital diagnoses. In this
         study, the participants also answered questions about their dietary
         habits.
   •     The study reports, in both women and men, a prudent diet is
         associated with lower disinhibition. In men, disinhibition is associated
         with meat and full-cream dairy consumption. Surprisingly, dietary
         restriction of wheat/eggs/dairy was also associated with higher
         disinhibition. This was unexpected as it is assumed disinhibition
         affects a person’s ability to restrict oneself. The author suggested
         multiple explanations for this including residual confounding caused
         by non-Western dietary patterns, high prevalence of food intolerance
         in impulsive individuals, effect of response tendency of highly
         impulsive individuals. All associations in this study were found to be
         very weak, and further research is required to better understand and
         confirm correlations.

   Hot Topic: New findings on ADHD trajectory from epidemiological
   studies

   001 - Trajectories of ADHD symptoms into adulthood: Data from five
   cohorts
   Rachel Blakey presents the results from an analysis of five international
   cohorts of ADHD patients. This study modelled the trajectory of illness
   based on level of symptoms (measured using DSM and SDQ).
   ADHD symptoms typically decline during adolescence, but not for all
   people. This study aimed to understand the trajectories of ADHD
   symptoms in the general population and describe how symptoms change
   across childhood, adolescence and into adulthood. The results suggest
   that overall, average symptoms decrease with age. The study also showed
   a slight uptick in severity of symptoms in ADHD patients between ages
   17-21, which requires further study to understand the explanation why.
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   002 - Genetic risk and ADHD trajectories across development
   • Dr. Jessica Agnew-Blais presents the results of two projects aiming to
      understand the association of genetic risk of ADHD and trajectories
      across development:
   • Polygenic risk and course of ADHD from childhood to young
      adulthood: findings from a nationally representative cohort.
   •     Polygenic risk and late-onset ADHD: A cross-cohort study
   •     These projects involved analysis of data from various cohorts,
         including the Environmental Risk Longitudinal (E-RISK) study based in
         the UK. These cohorts provided data on participant’s ADHD diagnosis
         (either through DSM-IV criteria or self/teacher/parent-report) and
         genetic data to allow calculation of ADHD polygenic risk score (PRS).
   •     From early childhood to adolescence, ADHD PRS is associated with an
         ADHD diagnosis and symptoms, but only explains a small amount of
         the variance. It also showed that during this time, ADHD PRS was
         consistently associated with elevated levels of symptoms, but had no
         association with the rate of change over time.
   •     From childhood to young adulthood, persistent ADHD was associated
         with higher ADHD PRS (but this association was not significantly
         different to the association between PRS and remitted ADHD). This
         study also showed that ADHD PRS is not elevated in patients with late-
         onset ADHD, which does not support the hypothesis that these cases
         were ‘missed’ in childhood. Also, analysis of young adults with
         persistent or late-onset ADHD (identified in multiple cohorts; E-Risk,
         Children of the 90s, Pelotas, The Dunedin study) showed that there is
         no elevated genetic risk for depression, alcohol dependence or
         cannabis use disorders in these patients.

   003 - The neurobiological signature of the at-risk state for ADHD
   • Dr Arthur Caye presents a study which aimed to replicate the risk
      score for adult ADHD in a Brazilian cohort, apply the risk score to
      separate individuals at low and high risk for ADHD, and compare these
      low and high risk groups in terms of neurobiology and psychological
      functioning.
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   •     The baseline sample included a community-based cohort of
         children (aged 6-14 years, N=2,511) who were assessed for their
         ADHD risk score (based on psychological assessment and
         neuroimaging), and then followed up until the age of 12-22 years.
   •     In comparison of the risk scores (assessed using genetics and
         neuropsychology) the relative risk of developing ADHD between
         unaffected low and high-risk score groups was 22.76. While,
         comparison of risk scores based on neuroimaging suggest the relative
         risk of developing ADHD between low and high-risk score groups is
         8.16. The neuroimaging analysis was based on relatively small sample
         sizes which limited the study and further analysis is required. The
         study concludes, based on the assessment of multiple risk factors,
         individuals who are at risk of ADHD have a higher genetic load, ADHD
         related brain alterations, and impaired neuropsychological
         functioning.

   004 - Predictors and outcomes of data-driven ADHD developmental
   trajectories across three cohorts
   • Aja Murray presents a study comparing the predictive characteristics
       and outcomes of patients with varying trajectories of ADHD which
       aims to find answers to the following questions.
   • Are there early markers of later-onset symptoms?
   • Are there clinically meaningful differences between later vs early
       onset subtypes?
   •     What differentiates those whose symptoms persist vs remit?
   •     The Millenium Cohort Study (MCS) includes parent-reported ADHD
         symptoms for children aged 3,5,7,11,14 (N=11,316). This dataset was
         analysed to understand the predictive characteristics of different
         ADHD profiles. Based on analysis of the MCS cohort, patients with late
         childhood/adolescent onset vs. pre-school onset were more likely to
         be female, have fewer conduct problems at age 3, and higher school
         readiness scores at age 3. Those with pre-school onset/persistent
         ADHD vs. partially remitting class were more likely to be male and had
         more conduct problems at age 3. Those with late

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        childhood/adolescent onset ADHD vs. those unaffected were
        more likely to be male, premature born, and had more conduct and
        peer problems age 3.
   •    The Zurich Project on social development from childhood to
        adulthood (z-proso) cohort includes teacher-reported ADHD
        symptoms data at ages 7-15 (N=1,572). This dataset was analysed to
        assess how outcomes (including prosociality, internalising, aggression,
        violent ideations, delinquency, cigarette smoking, alcohol use, and
        self-reported ADHD symptoms) vary by different ADHD trajectories. By
        late adolescence, both later onset and earlier onset/persistent ADHD
        categories scored significantly worse on a range of psychosocial
        outcomes vs. unaffected people. There were few significant
        differences between later vs. earlier onset ADHD categories.
   •     Overall, late onset ADHD subtype was evident in both cohorts and
         shows similar psychosocial outcomes to earlier onset ADHD by late
         adolescence. Late onset ADHD also shows more early markers relative
         to those who never develop symptoms, it seems to be more
         characteristic of females and may reflect delayed onset due to
         compensatory strengths.

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