The developmental course of attention-deficit/hyperactivity disorder : persistence, remission and emergence of symptoms from childhood to adulthood

Attention-deficit/Hyperactivity Disorder (ADHD) is a common neurodevelopmental disorder that affects children, adolescents and adults. Several adverse outcomes have been consistently associated with a diagnosis of ADHD at any point in life. In this thesis, we were dedicated to the study of the course of ADHD from childhood to adulthood focusing on three perspectives. First, we discuss the age at onset of ADHD. Historically, ADHD has first been identified and described in children. Prospective clinical studies of children with ADHD found that the disorder might persist throughout adulthood, and the concept of adult ADHD remained tied to a childhood-onset disorder. Diagnostic manuals included age at onset in childhood as a core criterion for a valid ADHD diagnosis in adolescence and adulthood. However, recent studies challenged the validity of this criterion, suggesting that many ADHD cases in adulthood might have had a late onset. In this thesis, we present our contribution to the field with original data from a longitudinal birth cohort in Brazil and a theoretical discussion on the evidence so far available on the matter. Second, our research tried to parse out children who are at high risk for either persisting with ADHD throughout adolescence (for those already affected) or developing ADHD during their development into young adulthood. While many risk factors are already known, the literature is heterogeneous, findings are sometimes contradictory, and there is little clinical translation from the evidence. We reviewed and meta-analyzed the evidence available on risk factors for ADHD persistence, providing summary estimates for several known risk factors. We then developed and validated a multivariable risk calculator that aggregated several of these risk factors into one accurate individualized risk prediction. This tool is intended for research and clinical use, and available on-line. Third, we investigated the relative immaturity effect, by which children who are born later in the school calendar year present are more frequently diagnosed with ADHD. We did so by reviewing and meta-analyzing the evidence available, and by analyzing data from three large community-based cohorts placed in Brazil. The effect of relative immaturity is a conceptual demonstration of the importance of developmental adaptations in the genesis or worsening of ADHD symptoms, which might influence its emergence along childhood, adolescence and adulthood.O Transtorno de Déficit de Atenção/Hiperatividade (TDAH) é um transtorno comum do neurodesenvolvimento que afeta crianças, adolescentes e adultos. O diagnóstico de TDAH estão consistentemente associados com desfechos adversos em qualquer idade. Nesta tese, nós nos dedicamos ao estudo do curso do TDAH da infância até a idade adulta, focando em três perspectivas. Primeiro, discutimos a idade de início do TDAH. Historicamente, o TDAH foi identificado e descrito pela primeira vez em crianças. Estudos clínicos prospectivos de crianças com TDAH descobriram que o transtorno pode persistir até a idade adulta, e o conceito de TDAH adulto permaneceu conectado a um transtorno de início na infância. Manuais diagnósticos incluíram idade de início na infância como um critério central para um diagnóstico válido de TDAH na adolescência e idade adulta. Entretanto, estudos recentes desafiaram a validade empírica deste critério, sugerindo que muitos casos de TDAH na idade adulta podem ter um início tardio. Nesta tese, apresentamos nossa contribuição nesta área com dados originais de uma coorte de nascimento no Brasil, e uma discussão teórica a respeito da evidência disponível sobre o assunto. Na segunda perspectiva, nossa pesquisa tentou identificar crianças que estão em risco para persistir com TDAH ao longo da adolescência (para aquelas já afetadas pelo transtorno) ou desenvolver TDAH ao longo do seu desenvolvimento até o início da idade adulta. Embora diversos fatores de risco sejam conhecidos, a literatura é heterogênea, os achados são por vezes contraditórios, e existe pouca tradução da evidência para a clínica. Nós revisamos e meta-analisamos a evidência disponível em fatores de risco para a persistência de TDAH, produzindo assim estimativas sumarizadas de risco para diversos fatores conhecidos. Em um segundo estudo, desenvolvemos e validamos uma calculadora de risco multivariada que agrega vários destes fatores em uma predição de risco individualizada e acurada. Esta ferramenta está disponível gratuitamente on-line, e pode ser usada em contextos clínicos e de pesquisa. Na terceira perspectiva, investigamos o efeito da imaturidade relativa, pelo qual crianças que nasceram mais tarde no ano letivo são mais frequentemente diagnosticadas com TDAH. Nós revisamos e meta-analisamos a evidência disponível, e analisando dados de três grandes coortes comunitárias no Brasil. O efeito da imaturidade relativa é uma demonstração conceitual da importância de adaptações desenvolvimentais na gênese de sintomas de TDAH, que podem influenciar sua emergência ao longo da infância, adolescência ou idade adulta

Decline in attention-deficit hyperactivity disorder traits over the life course in the general population : trajectories across five population birth cohorts spanning ages 3 to 45 years

Background Trajectories of attention-deficit hyperactivity disorder (ADHD) traits spanning early childhood to mid-life have not been described in general populations across different geographical contexts. Population trajectories are crucial to better understanding typical developmental patterns. Methods We combined repeated assessments of ADHD traits from five population-based cohorts, spanning ages 3 to 45 years. We used two measures: (i) the Strengths and Difficulties Questionnaire (SDQ) hyperactive-inattentive subscale (175 831 observations, 29 519 individuals); and (ii) scores from DSM-referenced scales (118 144 observations, 28 685 individuals). Multilevel linear spline models allowed for non-linear change over time and differences between cohorts and raters (parent/teacher/self). Results Patterns of age-related change differed by measure, cohort and country: overall, SDQ scores decreased with age, most rapidly declining before age 8 years (-0.157, 95% CI: -0.170, -0.144 per year). The pattern was generally consistent using DSM scores, although with greater between-cohort variation. DSM scores decreased most rapidly between ages 14 and 17 years (-1.32%, 95% CI: -1.471, -1.170 per year). Average scores were consistently lower for females than males (SDQ: -0.818, 95% CI: -0.856, -0.780; DSM: -4.934%, 95% CI: -5.378, -4.489). This sex difference decreased over age for both measures, due to an overall steeper decrease for males. Conclusions ADHD trait scores declined from childhood to mid-life, with marked variation between cohorts. Our results highlight the importance of taking a developmental perspective when considering typical population traits. When interpreting changes in clinical cohorts, it is important to consider the pattern of expected change within the general population, which is influenced by cultural context and measurement

Toward precision medicine in ADHD

Attention-Deficit Hyperactivity Disorder (ADHD) is a complex and heterogeneous neurodevelopmental condition for which curative treatments are lacking. Whilst pharmacological treatments are generally effective and safe, there is considerable inter-individual variability among patients regarding treatment response, required dose, and tolerability. Many of the non-pharmacological treatments, which are preferred to drug-treatment by some patients, either lack efficacy for core symptoms or are associated with small effect sizes. No evidence-based decision tools are currently available to allocate pharmacological or psychosocial treatments based on the patient's clinical, environmental, cognitive, genetic, or biological characteristics. We systematically reviewed potential biomarkers that may help in diagnosing ADHD and/or stratifying ADHD into more homogeneous subgroups and/or predict clinical course, treatment response, and long-term outcome across the lifespan. Most work involved exploratory studies with cognitive, actigraphic and EEG diagnostic markers to predict ADHD, along with relatively few studies exploring markers to subtype ADHD and predict response to treatment. There is a critical need for multisite prospective carefully designed experimentally controlled or observational studies to identify biomarkers that index inter-individual variability and/or predict treatment response

A risk calculator to predict adult Attention-deficit/Hyperactivity disorder::Generation and external validation in three birth cohorts and one clinical sample.

AimFew personalised medicine investigations have been conducted for mental health. We aimed to generate and validate a risk tool that predicts adult attention-deficit/hyperactivity disorder (ADHD).MethodsUsing logistic regression models, we generated a risk tool in a representative population cohort (ALSPAC - UK, 5113 participants, followed from birth to age 17) using childhood clinical and sociodemographic data with internal validation. Predictors included sex, socioeconomic status, single-parent family, ADHD symptoms, comorbid disruptive disorders, childhood maltreatment, ADHD symptoms, depressive symptoms, mother's depression and intelligence quotient. The outcome was defined as a categorical diagnosis of ADHD in young adulthood without requiring age at onset criteria. We also tested Machine Learning approaches for developing the risk models: Random Forest, Stochastic Gradient Boosting and Artificial Neural Network. The risk tool was externally validated in the E-Risk cohort (UK, 2040 participants, birth to age 18), the 1993 Pelotas Birth Cohort (Brazil, 3911 participants, birth to age 18) and the MTA clinical sample (USA, 476 children with ADHD and 241 controls followed for 16 years from a minimum of 8 and a maximum of 26 years old).ResultsThe overall prevalence of adult ADHD ranged from 8.1 to 12% in the population-based samples, and was 28.6% in the clinical sample. The internal performance of the model in the generating sample was good, with an area under the curve (AUC) for predicting adult ADHD of 0.82 (95% confidence interval (CI) 0.79-0.83). Calibration plots showed good agreement between predicted and observed event frequencies from 0 to 60% probability. In the UK birth cohort test sample, the AUC was 0.75 (95% CI 0.71-0.78). In the Brazilian birth cohort test sample, the AUC was significantly lower -0.57 (95% CI 0.54-0.60). In the clinical trial test sample, the AUC was 0.76 (95% CI 0.73-0.80). The risk model did not predict adult anxiety or major depressive disorder. Machine Learning approaches did not outperform logistic regression models. An open-source and free risk calculator was generated for clinical use and is available online at https://ufrgs.br/prodah/adhd-calculator/.ConclusionsThe risk tool based on childhood characteristics specifically predicts adult ADHD in European and North-American population-based and clinical samples with comparable discrimination to commonly used clinical tools in internal medicine and higher than most previous attempts for mental and neurological disorders. However, its use in middle-income settings requires caution

Schedule for Affective Disorders and Schizophrenia for School-Age Children - Present and Lifetime Version (K-SADS-PL), DSM-5 update: translation into Brazilian Portuguese

Brazilian governmental research funding agency Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq)Brazilian governmental research funding agency Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES)Brazilian governmental research funding agency Fundacao de Amparo a Pesquisa do Estado do Rio Grande do Sul (FAPERGS)ShireNovartisEli LillyJanssen-CilagUniv Fed Rio Grande do Sul, Fac Med, Dept Psiquiatria, Porto Alegre, RS, BrazilUniv Fed Rio Grande do Sul, Fac Med, Dept Pediat, Porto Alegre, RS, BrazilUniv Sao Paulo, Fac Med, Dept & Inst Psiquiatria, Sao Paulo, SP, BrazilUniv Fed Sao Paulo, Fac Med, Dept & Inst Psiquiatria, Sao Paulo, SP, BrazilPontifica Univ Catolica Rio Grande do Sul, Dev Cognit Neurosci Res Grp GNCD, Porto Alegre, RS, BrazilInst Bairral Psiquiatria, Ctr Integrado Desenvolvimento Infancia & Adolesce, Itapira, BrazilUniv Fed Sao Paulo, Fac Med, Dept & Inst Psiquiatria, Sao Paulo, SP, BrazilWeb of Scienc

Identifying adolescents at risk for depression: a prediction score performance in cohorts based in three different continents:A Prediction Score Performance in Cohorts Based in 3 Different Continents

OBJECTIVE: Prediction models have become frequent in the medical literature, but most published studies are conducted in a single setting. Heterogeneity between development and validation samples has been posited as a major obstacle for the generalization of models. We aimed to develop a multivariable prognostic model using sociodemographic variables easily obtainable from adolescents at age 15 to predict a depressive disorder diagnosis at age 18 and to evaluate its generalizability in 2 samples from diverse socioeconomic and cultural settings. METHOD: Data from the 1993 Pelotas Birth Cohort were used to develop the prediction model, and its generalizability was evaluated in 2 representative cohort studies: the Environmental Risk (E-Risk) Longitudinal Twin Study and the Dunedin Multidisciplinary Health and Development Study. RESULTS: At age 15, 2,192 adolescents with no evidence of current or previous depression were included (44.6% male). The apparent C-statistic of the models derived in Pelotas ranged from 0.76 to 0.79, and the model obtained from a penalized logistic regression was selected for subsequent external evaluation. Major discrepancies between the samples were identified, impacting the external prognostic performance of the model (Dunedin and E-Risk C-statistics of 0.63 and 0.59, respectively). The implementation of recommended strategies to account for this heterogeneity among samples improved the model’s calibration in both samples. CONCLUSION: An adolescent depression risk score comprising easily obtainable predictors was developed with good prognostic performance in a Brazilian sample. Heterogeneity among settings was not trivial, but strategies to deal with sample diversity were identified as pivotal for providing better risk stratification across samples. Future efforts should focus on developing better methodological approaches for incorporating heterogeneity in prognostic research

Decline in attention deficit hyperactivity disorder traits over the life-course in the general population:Trajectories across five population birth cohorts spanning ages 3 to 45 years

Background Trajectories of attention-deficit hyperactivity disorder (ADHD) traits spanning early childhood to mid-life have not been described in general populations across different geographical contexts. Population trajectories are crucial to better understanding typical developmental patterns. Methods We combined repeated assessments of ADHD traits from five population-based cohorts, spanning ages 3 to 45 years. We used two measures: (i) the Strengths and Difficulties Questionnaire (SDQ) hyperactive-inattentive subscale (175 831 observations, 29 519 individuals); and (ii) scores from DSM-referenced scales (118 144 observations, 28 685 individuals). Multilevel linear spline models allowed for non-linear change over time and differences between cohorts and raters (parent/teacher/self). Results Patterns of age-related change differed by measure, cohort and country: overall, SDQ scores decreased with age, most rapidly declining before age 8 years (-0.157, 95% CI: -0.170, -0.144 per year). The pattern was generally consistent using DSM scores, although with greater between-cohort variation. DSM scores decreased most rapidly between ages 14 and 17 years (-1.32%, 95% CI: -1.471, -1.170 per year). Average scores were consistently lower for females than males (SDQ: -0.818, 95% CI: -0.856, -0.780; DSM: -4.934%, 95% CI: -5.378, -4.489). This sex difference decreased over age for both measures, due to an overall steeper decrease for males. Conclusions ADHD trait scores declined from childhood to mid-life, with marked variation between cohorts. Our results highlight the importance of taking a developmental perspective when considering typical population traits. When interpreting changes in clinical cohorts, it is important to consider the pattern of expected change within the general population, which is influenced by cultural context and measurement

Polygenic risk score for attention-deficit/hyperactivity disorder and brain functional networks segregation in a community-based sample

Neuroimaging studies suggest that brain development mechanisms might explain at least some behavioural and cognitive attention-deficit/hyperactivity disorder (ADHD) symptoms. However, the putative mechanisms by which genetic susceptibility factors influence clinical features via alterations of brain development remain largely unknown. Here, we set out to integrate genomics and connectomics tools by investigating the associations between an ADHD polygenic risk score (ADHD-PRS) and functional segregation of large-scale brain networks. With this aim, ADHD symptoms score, genetic and rs-fMRI (resting-state functional magnetic resonance image) data obtained in a longitudinal community-based cohort of 227 children and adolescents were analysed. A follow-up was conducted approximately 3 years after the baseline, with rs-fMRI scanning and ADHD likelihood assessment in both stages. We hypothesised a negative correlation between probable ADHD and the segregation of networks involved in executive functions, and a positive correlation with the default-mode network (DMN). Our findings suggest that ADHD-PRS is correlated with ADHD at baseline, but not at follow-up. Despite not surviving for multiple comparison correction, we found significant correlations between ADHD-PRS and segregation of cingulo-opercular networks and DMN at baseline. ADHD-PRS was negatively correlated with the segregation level of cingulo-opercular networks but positively correlated with the DMN segregation. These directions of associations corroborate the proposed counter-balanced role of attentional networks and DMN in attentional processes. However, the association between ADHD-PRS and brain networks functional segregation was not found at follow-up. Our results provide evidence for specific influences of genetic factors on development of attentional networks and DMN. We found significant correlations between polygenic risk score for ADHD (ADHD-PRS) and segregation of cingulo-opercular networks and default-mode network (DMN) at baseline. ADHD-PRS was negatively correlated with the segregation level of cingulo-opercular networks but positively correlated with the DMN segregation