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

Late adolescent outcomes of different developmental trajectories of ADHD symptoms in a large longitudinal study

There exists substantial heterogeneity in the developmental trajectories of ADHD symptoms, with distinctions often made between persistent versus remittent, and early- versus late-onset. However, how these trajectories relate to late adolescent functioning and whether, in particular, later onset trajectories mark a milder subtype remains unclear. Building on earlier work that has examined early life predictors of ADHD symptom trajectories up to age 14, we applied latent class growth analysis to data from the UK Millennium Cohort Study (N = 10,262) to evaluate whether developmental trajectories of ADHD symptoms up to age 17 (from age 3) were similar to those identified up to age 14 and associated with differing levels of impairment in peer victimisation, mental health, substance use, and delinquency outcomes at age 17. Our optimal model included five trajectory groups, labelled unaffected (37.6%), mildly affected (34.8%), subclinical remitting (14.4%), adolescent onset (7.6%), and stable high (5.6%). Adolescent onset and stable high trajectories were similarly impaired across all outcomes, other than substance use. Subclinical remitting individuals were impaired on self-esteem and well-being compared to unaffected individuals. By the end of mid-adolescence, those with a later onset have similar impairments to those following an early onset/persistent trajectory. Residual impairment may remain for those on a remitting trajectory

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

Developmental trajectories of ADHD symptoms in a large population-representative longitudinal study

Background: Previous research has suggested that there is substantial heterogeneity in the developmental trajectories of ADHD symptoms. Sometimes qualitative distinctions between trajectories with different ages of onset and/or patterns of remission are made; however, little is known about the predictors and broader clinical meaningfulness of these candidate ‘developmental subtypes’ of ADHD symptoms. Methods: We applied latent class growth analysis to data from the UK Millennium Cohort Study (MCS; N=11,316; ages 3,5,7,11 and 14) to evaluate whether developmental trajectories of ADHD symptoms differing in early life predictors could be identified. Our optimal model included six trajectory groups, labelled unaffected (34.9% of the sample), mildly affected (24.1%), subclinical remitting (12.8%), pre-school onset partially remitting (14.1%), developmentally increasing (7.6%), and pre-school onset persistent (6.4%). Results: Factors such as gender, conduct problems, cognitive ability, maternal education, premature birth, peer problems, and school readiness scores differentiated between specific ADHD symptom trajectories. Conclusions: Taken together, our findings provide preliminary evidence that distinguishing different trajectories of ADHD symptoms could be clinically informative

The Origins of Mental Toughness – Prosocial Behavior and Low Internalizing and Externalizing Problems at Age 5 Predict Higher Mental Toughness Scores at Age 14

Background: The concept of mental toughness (MT) has gained increasing importance among groups other than elite athletes by virtue of its psychological importance and explanatory power for a broad range of health-related behaviors. However, no study has focused so far on the psychological origins of MT. Therefore, the aims of the present study were: to explore, to what extent the psychological profiles of preschoolers aged five were associated with both (1) MT scores and (2) sleep disturbances at age 14, and 3) to explore possible gender differences. Method: Nine years after their first assessment at age five (preschoolers), a total of 77 adolescents (mean age: 14.35 years; SD = 1.22; 42% females) took part in this follow-up study. At baseline, both parents and teachers completed the Strengths and Difficulties Questionnaire (SDQ), covering internalizing and externalizing problems, hyperactivity, negative peer relationships, and prosocial behavior. At follow-up, participants completed a booklet of questionnaires covering socio-demographic data, MT, and sleep disturbances. Results: Higher prosocial behavior, lower negative peer relationships, and lower internalizing and externalizing problems at age five, as rated by parents and teachers, were associated with self-reported higher MT and lower sleep disturbances at age 14. At age 14, and relative to males, females had lower MT scores and reported more sleep disturbances. Conclusion: The pattern of results suggests that MT traits during adolescence may have their origins in the pre-school years

Life Span Studies of ADHD—Conceptual Challenges and Predictors of Persistence and Outcome

There is a renewed interest in better conceptualizing trajectories of attention-deficit/hyperactivity disorder (ADHD) from childhood to adulthood, driven by an increased recognition of long-term impairment and potential persistence beyond childhood and adolescence. This review addresses the following major issues relevant to the course of ADHD in light of current evidence from longitudinal studies: (1) conceptual and methodological issues related to measurement of persistence of ADHD, (2) estimates of persistence rate from childhood to adulthood and its predictors, (3) long-term negative outcomes of childhood ADHD and their early predictors, and (4) the recently proposed new adult-onset ADHD. Estimates of persistence vary widely in the literature, and diagnostic criteria, sample characteristics, and information source are the most important factors explaining variability among studies. Evidence indicates that ADHD severity, comorbid conduct disorder and major depressive disorder, and treatment for ADHD are the main predictors of ADHD persistence from childhood to adulthood. Comorbid conduct disorder and ADHD severity in childhood are the most important predictors of adverse outcomes in adulthood among children with ADHD. Three recent population studies suggested the existence of a significant proportion of individuals who report onset of ADHD symptoms and impairments after childhood. Finally, we highlight areas for improvement to increase our understanding of ADHD across the life span

Predicting the incidence of depression in adolescence using a sociodemographic risk score: prospective follow-up of the IDEA-RiSCo study.

BACKGROUND: Adolescence constitutes a critical window for preventing depression, but efforts have mostly targeted single risk factors. The Identifying Depression Early in Adolescence Risk Score (IDEA-RS) integrates easily obtainable sociodemographic variables and has been able to predict future depression across diverse populations. However, its performance within a prospective cohort remains untested. OBJECTIVE: To evaluate the performance of the IDEA-RS in a prospective sample of adolescents participating in the IDEA Risk Stratified Cohort. METHODS: Using the IDEA-RS, we screened 7720 adolescents aged 14-16 years in 101 public schools in Porto Alegre, Brazil, and recruited 50 low-risk (LR) and 50 high-risk (HR) participants without depression. The incidence of depressive disorders over 3 years was assessed using the Schedule for Affective Disorders and Schizophrenia for School-Age Children. Statistical analysis involved Poisson regression with robust variance to estimate incidence rate ratios (IRRs) for depression onset. FINDINGS: In the HR group, 14/45 developed depression, in comparison to 5/43 in the LR group. Poisson regression analysis confirmed a higher probability of developing depression in the HR group compared with the LR group (IRR of 2.68, 95% CI 1.05 to 6.79, p=0.04). CONCLUSION: In a prospective cohort of Brazilian adolescents, the IDEA-RS effectively distinguished between those at HR and LR for developing depression. CLINICAL IMPLICATIONS: These results support the usefulness of an easy-to-administer sociodemographic composite risk score for stratifying the probability of developing depression among adolescents, a promising tool to be used in a variety of global contexts, including resource-limited settings

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