Development of a risk calculator to predict attention-deficit/hyperactivity disorder in very preterm/very low birth weight newborns.

BACKGROUND: Very preterm/very low birth weight (VP/VLBW) newborns can have lifelong morbidities, as attention-deficit/hyperactivity disorder (ADHD). Clinicians have no markers to discriminate which among those individuals will develop later ADHD, based only on the clinical presentation at birth. Our aim was to develop an individualized risk calculator for ADHD in VP/VLBW newborns. METHODS: This retrospective prognostic study included a consecutive sample of all VP/VLBW children (gestational age <32 weeks and/or birth weight <1.5 kg) born between 2010 and 2012 from a clinical cohort in a Brazilian tertiary care hospital. Children were clinically assessed at 6 years of age for ADHD using the Schedule for Affective Disorders and Schizophrenia for School-Age Children (K-SADS). The least absolute shrinkage and selection operator (LASSO) method was used for model-building. RESULTS: Ninety-six VP/VLBW children were assessed at 6 years of age (92% follow-up), of whom 32 (33%) were diagnosed with ADHD. The area under the ROC curve (AUC) for ADHD prediction based on seven parameters (late-onset sepsis confirmed by blood culture, necrotizing enterocolitis, neonatal seizures, periventricular leukomalacia, respiratory distress syndrome, length of hospital stay, and number of maternal ADHD symptoms) was .875 (CI, 0.800-0.942, p < .001; AUC corrected for optimism with bootstrapping: .806), a performance that is comparable to other medical risk calculators. Compared to approaches that would offer early intervention to all, or intervention to none, the risk calculator will be more useful in selecting VP/VLBW newborns, with statistically significant net benefits at cost:benefits of around 1:2 to around 10:6 (range of ADHD risk thresholds of 32%-62%, respectively). It also showed specificity for ADHD compared to other prevalent child psychopathologies. CONCLUSIONS: The risk calculator showed good performance for early identification of VP/VLBW newborns at high risk of future ADHD diagnosis. External validity in population-based samples is needed to extend clinical usefulness.

Assessing undertreatment and overtreatment/misuse of ADHD medications in children and adolescents across continents: A systematic review and meta-analysis.

A controversy exists on whether there is an over or underuse of medications for Attention-Deficit/Hyperactivity Disorder (ADHD). We conducted the first meta-analysis to estimate the rate of ADHD pharmacological treatment in both diagnosed and undiagnosed individuals. Based on a pre-registered protocol (CRD42018085233), we searched a broad set of electronic databases and grey literature. After screening 25,676 abstracts, we retained 36 studies including 104,305 subjects, from which 18 studies met our main analysis criteria. The pooled pharmacological treatment rates were 19.1 % and 0.9 % in school-age children/adolescents with and without ADHD, respectively. We estimated that for each individual using medication without a formal ADHD diagnosis, there are three patients with a formal diagnosis who might benefit from medication but do not receive it in the US. Our results indicate both overtreatment/misuse of medication in individuals without ADHD and pharmacological undertreatment in youths with the disorder. Our findings reinforce the need for public health policies improving education on ADHD and discussions on the benefits and limitations of ADHD medications.

Computerized Cognitive Training for ADHD as an Add-On Treatment to Stimulants: A Randomized Clinical Trial.

Objective: Computerized cognitive training (CCT) as add-on treatment to stimulants for ADHD core symptoms is scarcely investigated. The purpose of this study is to assess the effect of CCT in a randomized controlled clinical trial for ADHD in children and adolescents treated with stimulants. Method: Fifty-three participants aged 6 to 13 years receiving stimulant treatment and presenting ADHD residual symptoms were randomized either to a CCT (n = 29) or to a controlled nonactive condition (n = 24) for four sessions/week during 12 weeks. The main outcome measure was inattentive symptoms assessed using the Swanson, Nolan, and Pelham-IV (SNAP-IV) Scale. Secondary outcomes include, among others, hyperactive/impulsive symptoms and cognitive tests. Results: There were neither significant group differences on ADHD-inattentive symptoms after the intervention nor on both ADHD-hyperactivity/impulsivity symptoms and cognitive measures. Conclusion: Our study does not provide evidence for the benefits of cognitive training over nonactive training on core ADHD symptoms in medicated ADHD children and adolescents.

Does ADHD worsen inhibitory control in preschool children born very premature and/or with very low birth weight?

INTRODUCTION: Deficits in executive functioning, especially in inhibitory control, are present in children born very premature and/or with very low birth weight (VP/VLBW) and in children with attention-deficit/hyperactivity disorder (ADHD). OBJECTIVE: To evaluate whether ADHD imposes additional inhibitory control (IC) deficits in preschoolers born VP/VLBW. METHODS: 79 VP/VLBW (4 to 7 years) children were assessed for ADHD using the Schedule for Affective Disorders and Schizophrenia for School Aged Children - Present and Lifetime Version (K-SADS-PL). IC was measured with Conners' Kiddie Continuous Performance Test (K-CPT 2) and the Behavior Rating Inventory of Executive Function - Preschool Version (BRIEF-P).Results: No significant differences were found between ADHD (n = 24) and non-ADHD children (n = 55) for any of the measures (p = 0.062 to p = 0.903). Both groups had deficits in most K-CPT 2 scores compared to normative samples, indicating poor IC and inconsistent reaction times. CONCLUSIONS: ADHD does not aggravate IC deficits in VP/VLBW children. Either neuropsychological tasks and parent reports of executive functions (EFs) may not be sensitive enough to differentiate VP/VLBW preschoolers with and without ADHD, or these children's EFs are already so impaired that there is not much room for additional impairments imposed by ADHD.

Does ADHD worsen inhibitory control in preschool children born very premature and/or with very low birth weight?

Abstract Introduction Deficits in executive functioning, especially in inhibitory control, are present in children born very premature and/or with very low birth weight (VP/VLBW) and in children with attention-deficit/hyperactivity disorder (ADHD). Objective To evaluate whether ADHD imposes additional inhibitory control (IC) deficits in preschoolers born VP/VLBW. Methods 79 VP/VLBW (4 to 7 years) children were assessed for ADHD using the Schedule for Affective Disorders and Schizophrenia for School Aged Children - Present and Lifetime Version (K-SADS-PL). IC was measured with Conners' Kiddie Continuous Performance Test (K-CPT 2) and the Behavior Rating Inventory of Executive Function - Preschool Version (BRIEF-P).Results: No significant differences were found between ADHD (n = 24) and non-ADHD children (n = 55) for any of the measures (p = 0.062 to p = 0.903). Both groups had deficits in most K-CPT 2 scores compared to normative samples, indicating poor IC and inconsistent reaction times. Conclusions ADHD does not aggravate IC deficits in VP/VLBW children. Either neuropsychological tasks and parent reports of executive functions (EFs) may not be sensitive enough to differentiate VP/VLBW preschoolers with and without ADHD, or these children's EFs are already so impaired that there is not much room for additional impairments imposed by ADHD.

Effects of computerized cognitive training as add-on treatment to stimulants in ADHD: a pilot fMRI study.

The neurofunctional effects of Cognitive training (CT) are poorly understood. Our main objective was to assess fMRI brain activation patterns in children with ADHD who received CT as an add-on treatment to stimulant medication. We included twenty children with ADHD from a clinical trial of stimulant medication and CT (10 in medication + CT and 10 in medication + non-active training). Between-group differences were assessed in performance and in brain activation during 3 fMRI paradigms of working memory (N-back: 0-back, 1-back, 2-back, 3-back), sustained attention (Sustained Attention Task - SAT: 2 s, 5 s and 8 s delays) and inhibitory control (Go/No-Go). We found significant group x time x condition interactions in working memory (WM) and sustained attention on brain activation. In N-back, decreases were observed in the BOLD signal change from baseline to endpoint with increasing WM load in the right insula, right putamen, left thalamus and left pallidum in the CT compared to the non-active group; in SAT - increases in the BOLD signal change from baseline to endpoint with increasing delays were observed in bilateral precuneus, right insula, bilateral associative visual cortex and angular gyrus, right middle temporal, precentral, postcentral, superior frontal and middle frontal gyri in the CT compared to the non-active group. CT in ADHD was associated with changes in activation in task-relevant parietal and striato-limbic regions of sustained attention and working memory. Changes in brain activity may precede behavioral performance modifications in working memory and sustained attention, but not in inhibitory control.

Assessing causality in the association between attention-deficit/hyperactivity disorder and obesity: a Mendelian randomization study.

BACKGROUND/OBJECTIVES: Attention-deficit hyperactivity disorder (ADHD), one of the most common neurodevelopmental disorders in childhood and adolescence, is associated with obesity in observational studies. However, it is unclear whether ADHD contributes to, results from or is merely correlated with obesity. This study evaluates the presence and direction of a causal effect between ADHD and obesity. SUBJECTS/METHODS: We performed a bidirectional two-sample Mendelian randomization using summary data from consortia of genome-wide association studies to investigate if ADHD (N = 55,374) has a causal effect on body mass index (BMI) in childhood (N = 35,668) and adulthood (N = 322,154-500,000), and vice-versa. The main analysis was performed using the inverse variance weighted (IVW) method. As sensitivity analyses, we used other Mendelian randomization methods that are more robust to horizontal pleiotropy (i.e., MR-Egger, weighted mode, and penalized weighted median estimators), as well as stratified the analysis by the putative mechanisms of genetic instruments (i.e., pathways involved or not in neurological processes). RESULTS: The IVW method indicated a positive causal effect of BMI on ADHD: ß = 0.324 (95% CI 0.198 to 0.449, p < 0.001; expressed as change in ln(odds ratio) of ADHD per each additional SD unit of BMI). IVW estimates were directionally consistent with other methods. On the other hand, we did not find consistent evidence for a causal effect of ADHD genetic liability on BMI. CONCLUSIONS: The results suggested that higher BMI increases the risk of developing ADHD, but not the other way around.

Are ADHD medications under or over prescribed worldwide?: Protocol for a systematic review and meta-analysis.

INTRODUCTION: Attention-Deficit/Hyperactivity Disorder (ADHD) is a common neurodevelopmental disorder, characterized by age inappropriate and impairing levels of inattention and/or hyperactivity/impulsivity. Pharmacotherapy is an important part of the ADHD multimodal treatment. The extent to which ADHD is pharmacologically over or under treated worldwide is controversial. We aimed to estimate the pooled worldwide rate of ADHD pharmacological treatment in individuals with and without the disorder. METHOD AND ANALYSIS: We will include published or unpublished studies reporting the rates of ADHD pharmacological treatment in participants with and without ADHD of any age group. Population-based, cohort, or follow-up studies, as well as data from insurance health system and third-party reimbursements will be eligible. Searches will be performed in a large number of electronic databases, including Medline, Embase, CINAHL, Cochrane, PsycINFO, Web of Science, and Scopus. The primary outcome will be the prevalence of ADHD pharmacological treatment in individuals with ADHD and without ADHD. Two independent reviewers will perform the screening, and data extraction process. Study quality/bias will be assessed with the Newcastle-Ottawa scale by 2 independent reviewers. To test the robustness of the findings, we will perform a series of sensitivity and meta-regression analysis. Analyses will be performed with R and STATA software. ETHICS AND DISSEMINATION: No IRB approval will be necessary. The results of this systematic review and meta-analysis will be presented at international conferences and published in peer-reviewed journals. REGISTRATION AND STATUS: PROSPERO 2018 CRD42018085233.

Attention-Deficit/Hyperactivity Disorder and Very Preterm/Very Low Birth Weight: A Meta-analysis.

CONTEXT: Although very preterm (VP), extremely preterm (EP), very low birth weight (VLBW), and extremely low birth weight (ELBW) newborns seem to have a higher risk of later attention-deficit/hyperactivity disorder (ADHD), the magnitude of the risk is not well-defined. OBJECTIVE: To systematically review and meta-analyze the risk of VP/VLBW and EP/ELBW individuals to develop a ADHD categorical diagnosis or dimensional symptomatology compared with controls with normal weight and/or birth age. DATA SOURCES: We used PsycINFO, Medline, Embase, and Cochrane databases. STUDY SELECTION: We selected cross-sectional, prospective, or retrospective studies with no time or language restriction. DATA EXTRACTION: Independent reviewers screened and extracted data using predefined standard procedures. RESULTS: In 12 studies (N = 1787), researchers relying on a categorical diagnosis showed that both VP/VLBW and EP/ELBW subjects have a higher ADHD risk (odds ratio [OR] = 3.04 higher than controls; 95% confidence interval [CI] 2.19 to 4.21). In subgroup analyses, we demonstrated that the more extreme the cases, the higher the ORs (VP/VLBW: OR = 2.25 [95% CI 1.56 to 3.26]; EP/ELBW: OR = 4.05 [95% CI 2.38 to 6.87]). We drew data from 29 studies (N = 3504) on ADHD symptomatology and found significant associations with inattention (standardized mean difference [SMD] = 1.31, 95% CI 0.66 to 1.96), hyperactivity and impulsivity (SMD = 0.74, 95% CI 0.35 to 1.13), and combined symptoms (SMD = 0.55, 95% CI 0.42 to 0.68) when compared with controls. LIMITATIONS: Heterogeneity was significantly high for all analyses involving the 3 ADHD dimensions. CONCLUSIONS: With our results, we provide evidence that VP/VLBW subjects have an increased risk of ADHD diagnosis and symptomatology compared with controls, and these findings are even stronger in the EP/ELBW group. Future researchers should address which risk factors related to prematurity or low birth weight lead to ADHD.

Computerized cognitive training in children and adolescents with attention deficit/hyperactivity disorder as add-on treatment to stimulants: feasibility study and protocol description.

Background: Cognitive training has received increasing attention as a non-pharmacological approach for the treatment of attention deficit/hyperactivity disorder (ADHD) in children and adolescents. Few studies have assessed cognitive training as add-on treatment to medication in randomized placebo controlled trials. The purpose of this preliminary study was to explore the feasibility of implementing a computerized cognitive training program for ADHD in our environment, describe its main characteristics and potential efficacy in a small pilot study. Methods: Six ADHD patients aged 10-12-years old receiving stimulants and presenting residual symptoms were enrolled in a randomized clinical trial to either a standard cognitive training program or a controlled placebo condition for 12 weeks. The primary outcome was core ADHD symptoms measured using the Swanson, Nolan and Pelham Questionnaire (SNAP-IV scale). Results: We faced higher resistance than expected to patient enrollment due to logistic issues to attend face-to-face sessions in the hospital and to fill the requirement of medication status and absence of some comorbidities. Both groups showed decrease in parent reported ADHD symptoms without statistical difference between them. In addition, improvements on neuropsychological tests were observed in both groups - mainly on trained tasks. Conclusions: This protocol revealed the need for new strategies to better assess the effectiveness of cognitive training such as the need to implement the intervention in a school environment to have an assessment with more external validity. Given the small sample size of this pilot study, definitive conclusions on the effects of cognitive training as add-on treatment to stimulants would be premature.

Computerized cognitive training in children and adolescents with attention deficit/hyperactivity disorder as add-on treatment to stimulants: feasibility study and protocol description / Treinamento cognitivo para crianças e adolescentes com transtorno de déficit de atenção/hiperatividade como tratamento complementar aos psicoestimulantes: estudo de viabilidade e descrição de protocolo

Abstract Background Cognitive training has received increasing attention as a non-pharmacological approach for the treatment of attention deficit/hyperactivity disorder (ADHD) in children and adolescents. Few studies have assessed cognitive training as add-on treatment to medication in randomized placebo controlled trials. The purpose of this preliminary study was to explore the feasibility of implementing a computerized cognitive training program for ADHD in our environment, describe its main characteristics and potential efficacy in a small pilot study. Methods Six ADHD patients aged 10-12-years old receiving stimulants and presenting residual symptoms were enrolled in a randomized clinical trial to either a standard cognitive training program or a controlled placebo condition for 12 weeks. The primary outcome was core ADHD symptoms measured using the Swanson, Nolan and Pelham Questionnaire (SNAP-IV scale). Results We faced higher resistance than expected to patient enrollment due to logistic issues to attend face-to-face sessions in the hospital and to fill the requirement of medication status and absence of some comorbidities. Both groups showed decrease in parent reported ADHD symptoms without statistical difference between them. In addition, improvements on neuropsychological tests were observed in both groups - mainly on trained tasks. Conclusions This protocol revealed the need for new strategies to better assess the effectiveness of cognitive training such as the need to implement the intervention in a school environment to have an assessment with more external validity. Given the small sample size of this pilot study, definitive conclusions on the effects of cognitive training as add-on treatment to stimulants would be premature.

Resumo Introdução O treinamento cognitivo tem recebido atenção especial como abordagem não medicamentosa para o tratamento do transtorno de déficit de atenção/hiperatividade (TDAH) em crianças e adolescentes. Poucos estudos avaliaram o treinamento cognitivo como abordagem complementar à medicação em ensaios clínicos randomizados controlados por placebo. O objetivo deste estudo foi explorar a viabilidade para a implementação de um programa de treinamento cognitivo computadorizado, descrever suas características principais e potencial eficácia em um pequeno estudo piloto. Métodos Seis pacientes com TDAH entre 10-12 anos de idade, em uso de psicoestimulantes e apresentando sintomas residuais, foram recrutados e randomizados para um dos dois grupos (treinamento cognitivo ou placebo) por 12 semanas. O desfecho principal foram os sintomas nucleares do TDAH avaliados através do Questionário de Swanson, Nolan e Pelham (SNAP-IV). Resultados Encontramos maior resistência do que a esperada no recrutamento dos pacientes em função de problemas logísticos para atender às sessões presenciais no hospital assim como para preencherem os critérios de status medicamentoso e ausência de algumas comorbidades. Ambos os grupos apresentaram diminuição nos escores dos sintomas de TDAH reportados pelos pais, mas sem diferença estatística entre eles. Além disso, foi observada melhora nos testes neuropsicológicos em ambos os grupos - principalmente nas tarefas treinadas pelo programa. Conclusão Este protocolo revelou a necessidade de novas estratégias para melhor avaliar a eficácia do treinamento cognitivo tal como a necessidade de implementar a intervenção no ambiente escolar a fim de obter uma avaliação com maior validade externa. Devido ao pequeno tamanho amostral deste estudo, conclusões definitivas sobre os efeitos do treinamento cognitivo como abordagem complementar aos psicoestimulantes seriam prematuras.

Association Between ADHD and Obesity: A Systematic Review and Meta-Analysis.

OBJECTIVE: Impulsivity and inattention related to attention deficit hyperactivity disorder (ADHD) may increase food intake and, consequently, weight gain. However, findings on the association between obesity/overweight and ADHD are mixed. The authors conducted a meta-analysis to estimate this association. METHOD: A broad range of databases was searched through Aug. 31, 2014. Unpublished studies were also obtained. Study quality was rated with the Newcastle-Ottawa Scale. Random-effects models were used. RESULTS: Forty-two studies that included a total of 728,136 individuals (48,161 ADHD subjects; 679,975 comparison subjects) were retained. A significant association between obesity and ADHD was found for both children (odds ratio=1.20, 95% CI=1.05-1.37) and adults (odds ratio=1.55, 95% CI=1.32-1.81). The pooled prevalence of obesity was increased by about 70% in adults with ADHD (28.2%, 95% CI=22.8-34.4) compared with those without ADHD (16.4%, 95% CI=13.4-19.9), and by about 40% in children with ADHD (10.3%, 95% CI=7.9-13.3) compared with those without ADHD (7.4%, 95% CI=5.4-10.1). The significant association between ADHD and obesity remained when limited to studies 1) reporting odds ratios adjusted for possible confounding factors; 2) diagnosing ADHD by direct interview; and 3) using directly measured height and weight. Gender, study setting, study country, and study quality did not moderate the association between obesity and ADHD. ADHD was also significantly associated with overweight. Individuals medicated for ADHD were not at higher risk of obesity. CONCLUSIONS: This study provides meta-analytic evidence for a significant association between ADHD and obesity/overweight. Further research should address possible underlying mechanisms and the long-term effects of ADHD treatments on weight in individuals with both ADHD and obesity.

Prevalence of obesity in attention-deficit/hyperactivity disorder: study protocol for a systematic review and meta-analysis.

INTRODUCTION: An increasing number of clinical and epidemiological studies suggest a possible association between attention-deficit/hyperactivity disorder (ADHD) and obesity/overweight. However, overall evidence is mixed. Given the public health relevance of ADHD and obesity/overweight, understanding whether and to what extent they are associated is paramount to plan intervention and prevention strategies. We describe the protocol of a systematic review and meta-analysis aimed at assessing the prevalence of obesity/overweight in individuals with ADHD versus those without ADHD. METHODS AND ANALYSIS: We will include studies of any design (except case reports or case series) comparing the prevalence of obesity and/or overweight in children or adults with and without ADHD (or hyperkinetic disorder). We will search an extensive number of databases including PubMed, Ovid databases, Web of Knowledge and Thomson-Reuters databases, ERIC and CINAHL. No restrictions of language will be applied. We will also contact experts in the field for possible unpublished or in press data. Primary and additional outcomes will be the prevalence of obesity and overweight, respectively. We will combine ORs using random-effects models in STATA V.12.0. The quality of the study will be assessed primarily using the Newcastle-Ottawa Scale. Subgroup meta-analyses will be conducted according to participants' age (children vs adults) and study setting (clinical vs general population). We will explore the feasibility of conducting meta-regression analyses to assess the moderating effect of age, gender, socioeconomic status, study setting, geographic location of the study (low-income, middle-income countries vs high-income countries), definition of obesity, method to assess ADHD, psychiatric comorbidities and medication status. ETHICS AND DISSEMINATION: No ethical issues are foreseen. The results will be published in a peer-reviewed journal and presented at national and international conferences of psychiatry, psychology, obesity and paediatrics. REGISTRATION: PROSPERO-National Institute of Health Research (NIHR) Prospective Register of Systematic Reviews (CRD42013006410).