Polygenic association between attention-deficit/hyperactivity disorder liability and cognitive impairments.

BACKGROUND: A recent genome-wide association study (GWAS) identified 12 independent loci significantly associated with attention-deficit/hyperactivity disorder (ADHD). Polygenic risk scores (PRS), derived from the GWAS, can be used to assess genetic overlap between ADHD and other traits. Using ADHD samples from several international sites, we derived PRS for ADHD from the recent GWAS to test whether genetic variants that contribute to ADHD also influence two cognitive functions that show strong association with ADHD: attention regulation and response inhibition, captured by reaction time variability (RTV) and commission errors (CE). METHODS: The discovery GWAS included 19 099 ADHD cases and 34 194 control participants. The combined target sample included 845 people with ADHD (age: 8-40 years). RTV and CE were available from reaction time and response inhibition tasks. ADHD PRS were calculated from the GWAS using a leave-one-study-out approach. Regression analyses were run to investigate whether ADHD PRS were associated with CE and RTV. Results across sites were combined via random effect meta-analyses. RESULTS: When combining the studies in meta-analyses, results were significant for RTV (R2 = 0.011, ß = 0.088, p = 0.02) but not for CE (R2 = 0.011, ß = 0.013, p = 0.732). No significant association was found between ADHD PRS and RTV or CE in any sample individually (p > 0.10). CONCLUSIONS: We detected a significant association between PRS for ADHD and RTV (but not CE) in individuals with ADHD, suggesting that common genetic risk variants for ADHD influence attention regulation.

The risk of eating disorders comorbid with attention-deficit/hyperactivity disorder: A systematic review and meta-analysis.

OBJECTIVE: There has been interest in whether people with Attention-Deficit/Hyperactivity Disorder (ADHD) are at higher risk of developing an Eating Disorder (ED). The aim of this study was estimate the size of this association with a meta-analysis of studies. METHODS: We retrieved studies following PRISMA guidelines from a broad range of databases. RESULTS: Twelve studies fitted our primary aim in investigating ED in ADHD populations (ADHD = 4,013/Controls = 29,404), and five exploring ADHD in ED populations (ED = 1,044/Controls = 11,292). The pooled odds ratio of diagnosing any ED in ADHD was increased significantly, 3.82 (95% CI:2.34-6.24). A similar level of risk was found across all ED syndromes [Anorexia Nervosa = 4.28 (95% CI:2.24-8.16); Bulimia Nervosa = 5.71 (95% CI: 3.56-9.16) and Binge Eating Disorder = 4.13 (95% CI:3-5.67)]. The risk was significantly higher if ADHD was diagnosed using a clinical interview [5.89 (95% CI:4.32-8.04)] rather than a self-report instrument [2.23 (95% CI:1.23-4.03)]. The pooled odds ratio of diagnosing ADHD in participants with ED was significantly increased, 2.57 (95% CI:1.30-5.11). Subgroup analysis of cohorts with binge eating only yielded a risk of 5.77 (95% CI:2.35-14.18). None of the variables examined in meta-regression procedures explained the variance in effect size between studies. DISCUSSION: People with ADHD have a higher risk of comorbidity with an ED and people with an ED also have higher levels of comorbidity with ADHD. Future studies should address if patients with this comorbidity have a different prognosis, course and treatment response when compared to patients with either disorder alone. RESUMEN OBJETIVO: Ha habido interés en saber si la gente con Trastorno por Déficit de Atención e Hiperactividad (TDAH) están en mayor riesgo de desarrollar un Trastorno de la Conducta Alimentaria (TCA). El objetivo de este estudio fue estimar el tamaño de esta asociación con un meta-análisis de los estudios. Métodos: Recuperamos estudios de una amplia gama base de datos,  que siguen los lineamientos PRISMA. Resultados: Doce estudios encajaron con nuestro objetivo primario de investigar los TCA en poblaciones con TDAH (TDAH = 4,013/Controles = 29,404), y 5 exploraron TDAH en poblaciones con TCA (TCA = 1,044/Controles = 11,292). El odds ratio (OR) agrupado de diagnosticar cualquier TCA en el TDAH se incrementó significativamente, 3.82 (95% CI:2.34-6.24). Un nivel de riesgo similar fue encontrado en todos los síndromes de TCA [Anorexia Nervosa = 4.28 (95% CI:2.24-8.16); Bulimia Nervosa = 5.71 (95% CI:3.56-9.16) y Trastorno por Atracón = 4.13 (95% CI: 3-5.67)]. El riesgo fue significativamente mayor si el TDAH fue diagnosticado utilizando una entrevista clínica [5.89 (95% CI:4.32-8.04)] en lugar de un instrumento de auto-reporte [2.23 (95% CI:1.23-4.03)]. El odds ratio (OR) agrupado de diagnosticar TDAH en participantes con TCA fue significativamente incrementado, 2.57 (95% CI:1.30-5.11). El análisis de los subgrupos de cohort con atracones solamente produjo un riesgo de 5.77 (95% CI:2.35-14.18). Ninguna de las variables examinadas en los procedimientos de meta-regresión explicaron la varianza en el tamaño del efecto entre los estudios. Discusión: La gente con TDAH tiene un mayor riesgo de comorbilidad con un TCA y la gente con un TCA también tiene niveles altos de comorbilidad con TDAH. Los estudios futuros deberán abordar si los pacientes con esta comorbilidad tienen diferente pronóstico, curso y respuesta a tratamiento cuando son comparados con pacientes que solamente tienen uno de los trastornos.  © 2016 Wiley Periodicals, Inc. (Int J Eat Disord 2016) © 2016 Wiley Periodicals, Inc. (Int J Eat Disord 2016; 49:1045-1057).

Neurocognitive predictors of substance use disorders and nicotine dependence in ADHD probands, their unaffected siblings, and controls: a 4-year prospective follow-up.

BACKGROUND: Attention-Deficit/Hyperactivity Disorder (ADHD) is a risk factor for substance use disorders (SUDs) and nicotine dependence (ND). Neurocognitive deficits may predict the increased risk of developing SUDs and nicotine dependence. METHODS: This study comprised three groups derived from the Dutch part of the International Multicenter ADHD Genetics (IMAGE) study: ADHD probands (n = 294), unaffected siblings (n = 161), and controls (n = 214). At baseline (age = 12.2), a range of neurocognitive functions was assessed including executive functions (inhibition, working memory, timing), measures of motor functioning (motor timing and tracking) and IQ. After a mean follow-up of 4.2 years, SUDs and ND were assessed. RESULTS: None of the neurocognitive functions predicted later SUDs or ND in ADHD probands, even after controlling for medication use and conduct disorder. Slower response inhibition predicted later nicotine dependence in unaffected siblings (OR = 2.06, 95% CI = 1.22-3.48), and lower IQ predicted increased risk for SUDs in controls (OR = 1.96, 95% CI = 1.12-3.44). CONCLUSIONS: Cold executive functions, motor functioning, and IQ did not predict the elevated risk of SUDs and ND in ADHD. Future studies should target 'hot' executive functions such as reward processing as risk factors for SUDs or ND.

Multilevel analysis of ADHD, anxiety and depression symptoms aggregation in families.

A strong genetic role in the etiology of attention-deficit hyperactivity disorder (ADHD) has been demonstrated by several studies using different methodologies. Shortcomings of genetic studies often include the lack of golden standard practices for diagnosis for ADHD, the use of categorical instead of a dimensional approach, and the disregard for assortative mating phenomenon in parents. The current study aimed to overcome these shortcomings and analyze data through a novel statistical approach, using multilevel analyses with Bayesian procedures and a specific mathematical model, which takes into account data with an elevated number of zero responses (expected in samples with few or no ADHD symptoms). Correlations of parental clinical variables (ADHD, anxiety and depression) to offspring psychopathology may vary according to gender and type of symptoms. We aimed to investigate how those variables interact within each other. One hundred families, comprising a proband child or adolescent with ADHD or a typically developing child or adolescent were included and all family members (both biological parents, the proband child or adolescent and their sibling) were examined through semi-structured interviews using DSM-IV criteria. Results indicated that: (a) maternal clinical variables (ADHD, anxiety and depression) were more correlated with offspring variables than paternal ones; (b) maternal inattention (but not hyperactivity) was correlated with both inattention and hyperactivity in the offspring; (c) maternal anxiety was correlated with offspring inattention; on the other hand, maternal inattention was correlated with anxiety in the offspring. Although a family study design limits the possibility of revealing causality and cannot disentangle genetic and environmental factors, our findings suggest that ADHD, anxiety and depression are variables that correlate in families and should be addressed together. Maternal variables significantly correlated with offspring variables, but the paternal variables did not.

Influence of attention-deficit/hyperactivity disorder on binge eating behaviors and psychiatric comorbidity profile of obese women.

OBJECTIVE: Previous studies have reported higher prevalence rates of attention-deficit/hyperactivity disorder (ADHD) both in eating disorders (ED) and in obese patients. We compared the psychiatric comorbidity profile of obese ADHD women with non-ADHD obese women and how ADHD symptoms impact in binge eating behaviors. DESIGN: Cross-sectional study of a clinical sample. SUBJECTS: 171 adult women were evaluated at a specialized clinic in obesity and ED. MEASUREMENTS: Participants complete a semi-structured interview and psychopathology rating scales. A hierarchical regression model was employed to predict binge eating behavior. RESULTS: Obese ADHD patients had a larger number of psychiatric comorbidities (p<0.001), especially Substance Abuse Disorders, and higher scores on psychopathology rating scales (p<0.05). The highest prediction for binge eating in the regression model was the presence of depressive symptoms, followed by ADHD inattention symptoms and trait-impulsivity. CONCLUSION: ADHD should be routinely evaluated in obese since it is related with more severe psychopathology. Depressive symptoms can predict the presence of binge eating in obese patients.

Angiogenic, neurotrophic, and inflammatory system SNPs moderate the association between birth weight and ADHD symptom severity.

Low birth weight is associated with increased risk for Attention-Deficit/Hyperactivity Disorder (ADHD); however, the etiological underpinnings of this relationship remain unclear. This study investigated if genetic variants in angiogenic, dopaminergic, neurotrophic, kynurenine, and cytokine-related biological pathways moderate the relationship between birth weight and ADHD symptom severity. A total of 398 youth from two multi-site, family-based studies of ADHD were included in the analysis. The sample consisted of 360 ADHD probands, 21 affected siblings, and 17 unaffected siblings. A set of 164 SNPs from 31 candidate genes, representing five biological pathways, were included in our analyses. Birth weight and gestational age data were collected from a state birth registry, medical records, and parent report. Generalized Estimating Equations tested for main effects and interactions between individual SNPs and birth weight centile in predicting ADHD symptom severity. SNPs within neurotrophic (NTRK3) and cytokine genes (CNTFR) were associated with ADHD inattentive symptom severity. There was no main effect of birth weight centile on ADHD symptom severity. SNPs within angiogenic (NRP1 & NRP2), neurotrophic (NTRK1 & NTRK3), cytokine (IL16 & S100B), and kynurenine (CCBL1 & CCBL2) genes moderate the association between birth weight centile and ADHD symptom severity. The SNP main effects and SNP × birth weight centile interactions remained significant after adjusting for multiple testing. Genetic variability in angiogenic, neurotrophic, and inflammatory systems may moderate the association between restricted prenatal growth, a proxy for an adverse prenatal environment, and risk to develop ADHD.

Stimulant treatment for attention-deficit hyperactivity disorder and risk of developing substance use disorder.

BACKGROUND: Attention-deficit hyperactivity disorder (ADHD) is linked to increased risk for substance use disorders and nicotine dependence. AIMS: To examine the effects of stimulant treatment on subsequent risk for substance use disorder and nicotine dependence in a prospective longitudinal ADHD case-control study. METHOD: At baseline we assessed ADHD, conduct disorder and oppositional defiant disorder. Substance use disorders, nicotine dependence and stimulant treatment were assessed retrospectively after a mean follow-up of 4.4 years, at a mean age of 16.4 years. RESULTS: Stimulant treatment of ADHD was linked to a reduced risk for substance use disorders compared with no stimulant treatment, even after controlling for conduct disorder and oppositional defiant disorder (hazard ratio (HR) = 1.91, 95% CI 1.10-3.36), but not to nicotine dependence (HR = 1.12, 95% CI 0.45-2.96). Within the stimulant-treated group, a protective effect of age at first stimulant use on substance use disorder development was found, which diminished with age, and seemed to reverse around the age of 18. CONCLUSIONS: Stimulant treatment appears to lower the risk of developing substance use disorders and does not have an impact on the development of nicotine dependence in adolescents with ADHD.

Practitioner review: current best practice in the management of adverse events during treatment with ADHD medications in children and adolescents.

BACKGROUND: Medication is an important element of therapeutic strategies for ADHD. While medications for ADHD are generally well-tolerated, there are common, although less severe, as well as rare but severe adverse events AEs during treatment with ADHD drugs. The aim of this review is to provide evidence- and expert-based guidance concerning the management of (AEs) with medications for ADHD. METHODS: For ease of use by practitioners and clinicians, the article is organized in a simple question and answer format regarding the prevalence and management of the most common AEs. Answers were based on empirical evidence from studies (preferably meta-analyses or systematic reviews) retrieved in PubMed, Ovid, EMBASE and Web of Knowledge through 30 June 2012. When no empirical evidence was available, expert consensus of the members of the European ADHD Guidelines Group is provided. The evidence-level of the management recommendations was based on the SIGN grading system. RESULTS: The review covers monitoring and management strategies of loss of appetite and growth delay, cardiovascular risks, sleep disturbance, tics, substance misuse/abuse, seizures, suicidal thoughts/behaviours and psychotic symptoms. CONCLUSION: Most AEs during treatment with drugs for ADHD are manageable and most of the times it is not necessary to stop medication, so that patients with ADHD may continue to benefit from the effectiveness of pharmacological treatment.

Comorbid anxiety and neurocognitive dysfunctions in children with ADHD.

Previous research established that children with ADHD and comorbid anxiety have a later age of ADHD onset, show less off-task and hyperactive behavior, and have more school problems than children with ADHD alone. Comorbid anxiety appears to ameliorate behavioral inhibition deficits, worsen working memory problems, and lengthen reaction times in ADHD. This study investigated the effect of comorbid anxiety on a broad range of neurocognitive functions and includes child-, parent- and teacher reports of anxiety. The sample consisted of 509 children in the age range 5-19 years, including 238 children with a diagnosis of ADHD combined subtype and 271 normal control children. Children were tested on a broad battery of neurocognitive tasks that proved highly sensitive to ADHD in previous work. Linear Structural Equation Modeling (SEM) was used to estimate the effect of comorbid anxiety on the neurocognitive functions. Child reported anxiety was associated with slower motor speed and response speed and better behavioral inhibition. Teacher reported anxiety was related to worse time production. Parent reported anxiety was not significantly associated with any of the neurocognitive functions. Compared to parent and teacher reports of anxiety, child reported comorbid anxiety shows foremost the largest associations with the neurocognitive dysfunctions observed in children with ADHD. This stresses the importance of including child self-reported anxiety assessments in clinical and research practice.

Aetiology for the covariation between combined type ADHD and reading difficulties in a family study: the role of IQ.

BACKGROUND: Twin studies using both clinical and population-based samples suggest that the frequent co-occurrence of attention deficit hyperactivity disorder (ADHD) and reading ability/disability (RD) is largely driven by shared genetic influences. While both disorders are associated with lower IQ, recent twin data suggest that the shared genetic variability between reading difficulties and ADHD inattention symptoms is largely independent from genetic influences contributing to general cognitive ability. The current study aimed to extend the previous findings that were based on rating scale measures in a population sample by examining the generalisability of the findings to a clinical population, and by measuring reading difficulties both with a rating scale and with an objective task. This study investigated the familial relationships between ADHD, reading difficulties and IQ in a sample of individuals diagnosed with ADHD combined type, their siblings and control sibling pairs. METHODS: Multivariate familial models were run on data from 1,789 individuals at ages 6-19. Reading difficulties were measured with both rating scale and an objective task. IQ was obtained using the Wechsler Intelligence Scales (WISC-III/WAIS-III). RESULTS: Significant phenotypic (.2-.4) and familial (.3-.5) correlations were observed among ADHD, reading difficulties and IQ. Yet, 53%-72% of the overlapping familial influences between ADHD and reading difficulties were not shared with IQ. CONCLUSIONS: Our finding that familial influences shared with general cognitive ability, although present, do not account for the majority of the overlapping familial influences on ADHD and reading difficulties extends previous findings from a population-based study to a clinically ascertained sample with combined type ADHD.