The 8th World Congress on ADHD (2021) - Post-Conference Wrap Up - Doctor Unite
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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 Information Classification: General informa | Pharma Intelligence 2
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
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). Information Classification: General informa | Pharma Intelligence 4
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): Information Classification: General informa | Pharma Intelligence 5
2021 ADHD World Congress Post-Conference Wrap Up • Interestingly, genetic overlap of ADHD occurs as well with many non- psychiatric diseases: Information Classification: General informa | Pharma Intelligence 6
2021 ADHD World Congress Post-Conference Wrap Up • 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. Information Classification: General informa | Pharma Intelligence 7
2021 ADHD World Congress Post-Conference Wrap Up 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
2021 ADHD World Congress Post-Conference Wrap Up was not met at the beginning (30 minutes) and end (12-13 hours) when assessing SKAMP-C with visit 5 as the baseline. Information Classification: General informa | Pharma Intelligence 9
2021 ADHD World Congress Post-Conference Wrap Up • 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 Information Classification: General informa | Pharma Intelligence 10
2021 ADHD World Congress Post-Conference Wrap Up 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
2021 ADHD World Congress Post-Conference Wrap Up • 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
2021 ADHD World Congress Post-Conference Wrap Up 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. Information Classification: General informa | Pharma Intelligence 13
2021 ADHD World Congress Post-Conference Wrap Up • 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? Information Classification: General informa | Pharma Intelligence 14
2021 ADHD World Congress Post-Conference Wrap Up • 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. Information Classification: General informa | Pharma Intelligence 15
2021 ADHD World Congress Post-Conference Wrap Up 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. Information Classification: General informa | Pharma Intelligence 16
2021 ADHD World Congress Post-Conference Wrap Up • 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 Information Classification: General informa | Pharma Intelligence 17
2021 ADHD World Congress Post-Conference Wrap Up 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. Information Classification: General informa | Pharma Intelligence 18
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