Attention-deficit/hyperactivity disorder across development: epidemiology, etiology, and treatment

Author(s)

Luis Carlos Farhat

• Document type: Doctoral Thesis
• Press: São Paulo.
• Institution: Universidade de São Paulo (USP). Faculdade de Medicina (FM/SBD)
• Defense date: 2023-11-28

Examining board members

Guilherme Vanoni Polanczyk; Alicia Matijasevich Manitto; Luis Augusto Paim Rohde; Wallace Philip Shaw

• Advisor: Guilherme Vanoni Polanczyk

Abstract

In this thesis, there are six studies that were conducted to fill important gaps in the current state of knowledge about the epidemiology and clinical presentation, etiology, and pharmacotherapy of attention-deficit/hyperactivity disorder (ADHD) across development. In Chapter 3, which is focused on epidemiology and clinical presentation, we considered data from the Global Burden of Disease Study (GBD) 2019. Specifically, we reanalyzed its data with similar methods to those previously adopted in other systematic reviews and meta-analyses to critically evaluate the validity of the GBD2019 prevalence estimate for ADHD. Our results demonstrated that the pooled prevalence of ADHD was 5.41%, which was closer to the prevalence previously found in another systematic review (~6%) and approximately 2 times the prevalence reported by GBD2019 for the corresponding year (2.68%). We suggest that future editions of the GBD should indicate with greater transparency the possible impact of the statistical methods that they adopt on their results. In Chapter 4, which is related to epidemiology and clinical presentation, we investigated whether the associations between ADHD symptoms in childhood and depressive symptoms across development are specific, or confounded by other neurodevelopmental traits, emotional dysregulation, or socioenvironmental stressors highly correlated with ADHD symptoms. We estimated Gaussian graphical models on data from two UK cohorts, the Twins Early Development Study (4,407 individuals) and the Avon Longitudinal Study of Parents and Children (10,351 individuals). In both cohorts, we found significant bivariate correlations between ADHD and depressive symptoms; however, based on data replicated across cohorts, these pairs of variables were mostly conditionally independent, and none were conditionally associated, after accounting for the effects of socioenvironmental stressors, emotional dysregulation. These, in turn, were associated with both ADHD symptoms and depressive symptoms, indicating that the associations between ADHD and depressive symptoms could be explained by socioenvironmental stressors and emotional dysregulation. These findings should inform future studies focusing on the prevention of depression in the context of ADHD. In chapter 5, which is focused on etiology, we evaluate whether there is an enrichment of deleterious spontaneous rare variants in ADHD. We performed whole-exome sequencing of 152 parent-offspring trios with ADHD and identified a relative risk of 1.55 (95% confidence interval [CI] 1.02, 2.30). By combining our results with a case-control study involving more than 3,000 individuals with ADHD and 5,000 controls, we identified the lysine demethylase 5B (KDM5B) gene as a high-confidence risk gene for ADHD. These results contribute new information about the genetic architecture of ADHD and highlight the potential of the methodology that we employed to identify new risk genes in future studies. In Chapters 6 through 8, which are focused on pharmacotherapy, we investigate the effects of stimulants on the management of ADHD across development. Specifically, we conducted three systematic reviews and meta-analyses of randomized placebo-controlled clinical trials. In preschoolers, we demonstrated that stimulants had a moderate effect size in reducing ADHD symptoms (standardized mean difference 0.59, 95% CI 0.41, 0.77), reinforcing that these medications should be considered as an option in the treatment of ADHD in this population. In school-aged children and adolescents, we demonstrated that optimizing doses with escalation, as necessary and tolerated, up to the maximum limits licensed by regulatory agencies (e.g., the FDA) ensured greater reductions in ADHD symptoms and lower risks of discontinuing the treatment, reinforcing the importance of this practice in the treatment of ADHD in this age group. Lastly, in adults, we demonstrated that doses above the limits licensed by the FDA may not have favorable risk-benefits, and thus, practitioners should consider such high doses cautiously being mindful that additional gains in ADHD symptom reductions may be small with further increments in doses beyond licensed limits. In conclusion, the studies presented in this thesis generated advances in the current state of knowledge about several relevant aspects of ADHD. The results will contribute to the planning of services and prioritization of resources in health systems, development of new therapeutic strategies and optimization of pharmacological interventions available in the current scenario for the treatment of ADHD throughout development (AU)

• FAPESP's process: 21/08540-0 - Evaluation of the effects of treatment with methylphenidate compared with parental training in preschool children with ADHD on the path of cognitive, social, emotional and psychopathological development
• Grantee: Luis Carlos Farhat
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)