Polymorphisms in the dopamine D4 receptor gene and attention-deficit hyperactivity disorder

There is considerable evidence to support a role of dopamine-related genes in the molecular aetiology of attention-deficit hyperactivity disorder (ADHD). A 48 bp repeat in exon three of the dopamine D4 receptor gene has been widely studied in clinical ADHD samples, and a meta-analysis of published studies suggests it is associated with ADHD. A number of other polymorphisms across this gene have been characterised but not so thoroughly investigated in relation to ADHD. In this study we have genotyped five polymorphisms (a 120 bp promoter-region duplication, the -616 C/G substitution, the -521 C/T substitution, a poly-G repeat in intron 1, and the 48 bp exon 3 repeat) across the gene in a large clinical sample (n = 188) and their families. We found that none of the markers is individually associated with ADHD, although there is evidence to suggest that a haplotype of markers in the 5' promoter region of the gene (allele 2 of the 120 bp duplication, the C allele of the -616 substitution, and the C allele of the -521 substitution) may confer susceptibility.     

Linkage of the dopamine D4 receptor gene and attention-deficit/hyperactivity disorder

OBJECTIVE: There is considerable evidence supporting a genetic component in the etiology of attention-deficit/hyperactivity disorder (ADHD). Because stimulant medications act primarily on the dopaminergic system, dopamine system genes are prime candidates for genetic susceptibility factors for ADHD. Previous studies by several groups have observed a significant association of ADHD and an allele with 7 copies of the 48 base pair repeat in the third exon of the dopamine D4 receptor. METHOD: The authors sought to replicate these previous findings by collecting an independent sample of families from Toronto, Ontario, Canada, and confirming this finding in an expanded sample of ADHD families collected from Irvine, California. Using the transmission disequilibrium test (TDT), the authors tested for biased transmission of the 7-repeat allele at the exon III polymorphism of the dopamine D4 receptor locus in these samples of ADHD subjects. RESULTS: Biased transmission of the 7-repeat allele from parents to ADHD probands and their affected siblings was observed in the 2 new samples of families collected in Toronto and Irvine (TDT chi2 = 2.711, 1 df, one-sided p value = .050) and for these samples combined with the 52 families previously reported from Irvine (TDT chi2 = 6.426, 1 df, one-sided p value = .006). CONCLUSIONS: The results of this study further support the possibility of a role of the dopamine D4 receptor locus in ADHD.     

Linkage of the dopamine receptor D1 gene to attention-deficit/hyperactivity disorder

Attention-deficit/hyperactivity disorder (ADHD) has a strong genetic basis, and evidence from human and animal studies suggests the dopamine receptor D1 gene, DRD1, to be a good candidate for involvement. Here, we tested for linkage of DRD1 to ADHD by examining the inheritance of four biallelic DRD1 polymorphisms [D1P.5 (-1251HaeIII), D1P.6 (-800HaeIII), D1.1 (-48DdeI) and D1.7 (+1403Bsp1286I)] in a sample of 156 ADHD families. Owing to linkage disequilibrium between alleles at the four markers, only three haplotypes are common in our sample. Using the transmission/disequilibrium test (TDT), we observed a strong bias for transmission of Haplotype 3 (1.1.1.2) from heterozygous parents to their affected children (P=0.008). Furthermore, using quantitative trait TDT analyses, we found significant and positive relationships between Haplotype 3 transmission and the inattentive symptoms, but not the hyperactive/impulsive symptoms, of ADHD. These findings support the proposed involvement of DRD1 in ADHD, and implicate Haplotype 3, in particular, as containing a potential risk factor for the inattentive symptom dimension of the disorder. Since none of the four marker alleles comprising Haplotype 3 is predicted to alter DRD1 function, we hypothesize that a functional DRD1 variant, conferring susceptibility to ADHD, is on this haplotype. To search for such a variant we screened the DRD1 coding region, by sequencing, focusing on the children who showed preferential transmission of Haplotype 3. DNA from 41 children was analysed, and no sequence variations were identified, indicating that the putative DRD1 risk variant for ADHD resides outside of the coding region of the gene.     

Modafinil in children with attention-deficit hyperactivity disorder

Previous clinical evidence suggested that modafinil may improve clinical features of children with attention-deficit hyperactivity disorder. To test this hypothesis, a randomized, double-blind, placebo-controlled study design was used. Of 24 children initially randomized into the study, 11 control subjects and 11 treatment patients completed the study, with evaluation before medication and after 5 to 6 weeks. The average Test of Variables of Attention attention-deficit hyperactivity disorder z score improved by 2.53 S.D.s for the modafinil group compared with a decline of 1.02 for control patients (P < or = 0.02). Conners Rating Scales ADHD total t scores for the modafinil group improved from 76.6 to 68.2 compared with improvement from 77.7 to 76.0 for control subjects (P = 0.04). Ten of 11 treatment patients were reported as "significantly" improved, whereas eight of 11 control subjects were reported as manifesting "no" or "slight" improvement (P < 0.001). Adverse effects were few and manageable, with no anorexia. Modafinil may be a useful treatment for children with ADHD, particularly when anorexia limits use of stimulants.     

Polymorphisms of the dopamine D4 receptor, clinical outcome, and cortical structure in attention-deficit/hyperactivity disorder

CONTEXT: Attention-deficit/hyperactivity disorder (ADHD) is one of the most heritable neuropsychiatric disorders, and a polymorphism within the dopamine D4 receptor (DRD4) gene has been frequently implicated in its pathogenesis. OBJECTIVE: To examine the effects of the 7-repeat microsatellite in the DRD4 gene on clinical outcome and cortical development in ADHD. We drew comparisons with a single nucleotide polymorphism in the dopamine D1 receptor (DRD1) gene, which was associated with ADHD within our cohort, and a polymorphism within the dopamine transporter (DAT1) gene, reported to have additive effects with the DRD4 7-repeat allele. DESIGN: Longitudinal cohort study. SETTING: National Institutes of Health, Bethesda, Maryland. PARTICIPANTS: One hundred five children (with 222 neuroanatomical magnetic resonance images) with ADHD (mean age at entry, 10.1 years) and 103 healthy controls (total of 220 magnetic resonance images). Sixty-seven subjects with ADHD (64%) had follow-up clinical evaluations (mean follow-up, 6 years). MAIN OUTCOME MEASURES: Cortical thickness across the cerebrum and presence of DSM-IV-defined ADHD at follow-up. RESULTS: Possession of the DRD4 7-repeat allele was associated with a thinner right orbitofrontal/inferior prefrontal and posterior parietal cortex. This overlapped with regions that were generally thinner in subjects with ADHD compared with controls. Participants with ADHD carrying the DRD4 7-repeat allele had a better clinical outcome and a distinct trajectory of cortical development. This group showed normalization of the right parietal cortical region, a pattern that we have previously linked with better clinical outcome. By contrast, there were no significant effects of the DRD1 or DAT1 polymorphisms on clinical outcome or cortical development. CONCLUSIONS: The DRD4 7-repeat allele, which is widely associated with a diagnosis of ADHD, and in our cohort with better clinical outcome, is associated with cortical thinning in regions important in attentional control. This regional thinning is most apparent in childhood and largely resolves during adolescence.     

Serum ferritin in children with attention-deficit hyperactivity disorder

To further define a role for iron deficiency in attention-deficit hyperactivity disorder, serum ferritin was included in a battery of laboratory tests obtained in children attending a clinic for attention deficit disorders. In a total of 68 consecutive patients (ages 5-16 years; 54 male, 14 female), the range of serum ferritin levels was a low of 7.7 ng/mL and a high of 150 ng/mL. The mean (+/-S.D.) serum ferritin level in patients with attention-deficit hyperactivity disorder (39.9 +/- 40.6 ng/mL) was not different from that of control subjects. Seventy-four percent of patients had serum ferritin levels below 50 ng/mL; 44% were below 30 ng/mL; and 18% below 20 ng/mL. None had evidence of iron deficiency anemia. A comparison of the clinical characteristics of the 12 patients with the lowest serum ferritin levels (<20 ng/mL) and 12 with the highest levels (>60 ng/mL) disclosed no significant difference in severity or frequency of attention-deficit hyperactivity disorder and comorbid symptoms or response to medications. In this patient cohort, a causative role for low serum ferritin in attention-deficit hyperactivity disorder has not been confirmed.     

多巴胺D4受体基因多态性与注意缺陷多动障碍的关联分析

目的探讨注意缺陷多动障碍(ADHD)与多巴胺D4受体(DRD4)基因第3外显子48bp可变数目顺向重复(VNTR)多态性的关系.方法对176例ADHD患儿(病例组)、98个ADHD核心家系(家系组,共294人)及119名正常对照(对照组)进行ADHD与DRD4基因48bpVNTR多态性的关联分析.结果所测人群中的48bpVNTR多态性表现为2～6次重复(分别为407、bp、455bp、503bp、551bp及599bp);其中以4次重复(73.9%)和2次重复(21.8%)最为常见;尚未发现7次重复序列.病例组2/2基因型(6.3%)显著低于对照组(14.3%;P=0.02),这种差异主要表现在ADHD混合型.对98个家系的精确多等位基因不平衡传递检验,未发现等位基因与ADHD存在连锁不平衡(x2=5.119,v=4,P＞0.05).结论DRD4基因48bpVNTR多态性主要集中于4次重复序列片段上;48bp片段的重复次数可能与ADHD相关,重复2次时可以减少ADHD的易患性.     

Aggression in children with attention-deficit/hyperactivity disorder

Research shows that aggression is an important associated feature of attention-deficit/hyperactivity disorder (ADHD) and is important in understanding the impact of the disorder and its treatment. The occurrence of aggressive behavior in combination with ADHD does not appear to be spurious and the severity and/or presence of aggression and ADHD may significantly impact long-term prognosis. This article defines subtypes of aggression in relation to ADHD, identifies individual differences contributing to aggressive behavior in children with ADHD and discusses selected possible underlying mechanisms of aggression in ADHD, as well as current and emerging treatment approaches. Although aggressive behavior in children with ADHD is common, the reasons for this are not yet well understood. Multidisciplinary research should focus on investigating underlying mechanisms related to aggression in ADHD, as well as the utility of various treatment modalities.     

Cognition in African children with attention-deficit hyperactivity disorder

The aims of the study were: (1) to describe the performance of African children with symptoms of attention-deficit hyperactivity disorder on selected neuropsychologic tests and compare it with performance among peers of the same age without symptoms; (2) to explore through a factor analysis if the selected tests cover the same functions as known from studies in Europe and North America. A nested case-control approach was used to select the two groups of children. The tests were selected to measure aspects of executive functions, attention and memory functions as well as motor skills. A total of 185 schoolchildren (28 cases and 157 control subjects) aged 85 to 119 months old were included. The findings indicate only minor difference between children with symptoms of attention-deficit hyperactivity disorder and control subjects in most of the tasks. However, children with symptoms of attention-deficit hyperactivity disorder performed more poorly on tests of motor skills and had more violations of rules on the planning task. The factor analysis indicated a three-factor model, confirming that the selected tests could be used as measures of executive/motor functions, attention, and memory functions. Similar findings have been reported among children in Europe and North America.     

Mathematical learning disorder in school-age children with attention-deficit hyperactivity disorder

OBJECTIVES: To explore the prevalence of mathematics disorder (MD) relative to reading disorders (RD) in school-age children with attention-deficit hyperactivity disorder (ADHD) and examine the effects of age, sex, cooccurring conduct disorder (CD), and ADHD subtype on this comorbidity. METHODS: Participants were school-age children (n = 476) with confirmed DSM-IV diagnosis of ADHD. The assessment included semistructured parent and teacher interviews and standardized measures of intelligence, academic attainment, and language abilities. Based on the presence or absence of concurrent learning disorders, we compared the emerging 4 groups: ADHD-only, ADHD + MD, ADHD + RD, and ADHD + MD + RD. RESULTS: Overall prevalence of comorbid ADHD + MD was 18.1%. Age, sex, ADHD subtypes, or comorbid CD did not affect the frequency of MD. Children with concurrent ADHD and either MD or RD attained lower IQ, language, and academic scores than those with ADHD alone. Children with ADHD + MD + RD were more seriously impaired and demonstrated distinct deficits in receptive and expressive language. CONCLUSION: MDs are relatively common in school-age children with ADHD and are frequently associated with RDs. Children with ADHD + MD + RD are more severely impaired. These deficits simply cannot be explained as consequences of ADHD and might have unique biological underpinnings, with implications for diagnostic classification and therapeutic interventions.     

A pilot study of methylphenidate preference assessment in children diagnosed with attention-deficit/hyperactivity disorder

OBJECTIVE: The use of methylphenidate (MPH) in the treatment of attention-deficit/hyperactivity disorder (ADHD) is widely accepted; however, there is increased concern regarding its abuse potential. Few studies have examined the reinforcing effects of drugs in individuals receiving them for clinical purposes. This study attempts to assess MPH preference in children with ADHD using a choice procedure in order to explore the relationship among drug preference, clinical efficacy, and abuse potential. METHODS: Participants were 5 children (10-14 years of age) receiving MPH for the treatment of ADHD. Reinforcing effects were assessed using a double-blind choice procedure, with six sampling sessions and six choice sessions. Participant-rated effects were measured using self-report questionnaires. Clinical effects were measured using direct observations and behavior ratings. RESULTS: Differences between the number of MPH, Placebo, and Neither choices across participants were significant (chi2 = 9.6; p < 0.01). Three of five participants reliably chose MPH more often than placebo. MPH produced idiosyncratic patterns of participant-rated effects but failed to produce significant clinical effects. CONCLUSIONS: These findings add to the literature on the reinforcing effects of MPH and are the first reported in a clinical sample of children. Further research exploring the role of clinical efficacy in MPH preference is warranted.     

Developmental brain anomalies in children with attention-deficit hyperactivity disorder

The pathoetiology of attention-deficit hyperactivity disorder (ADHD) has been considered to be neurodevelopmental, yet the timing and processes involved are not clearly identified. Neurodevelopmental brain anomalies have been associated with a variety of psychiatric conditions. However, they have never been evaluated in a population of patients with ADHD. This study was designed to determine the frequency of specific developmental brain anomalies in a group of children with ADHD (n = 85; mean age, 10.9 years) and healthy control children (n = 95; mean age, 11.7 years) by visually inspecting brain magnetic resonance imaging scans. Compared to controls, the ADHD group showed an increase in frequency of two developmental anomalies: (1) gray-matter heterotopia, a neuronal migration anomaly, in 2 of 85 patients versus 0 of 95 controls; and (2) posterior fossa abnormality (excess cerebrospinal fluid in the posterior fossa) in 8 of 85 patients versus 2 of 95 controls. There were no differences in frequency of enlarged cavum septi pellucidi between the two groups. These findings support and extend the idea that ADHD is of developmental origin, and further suggest that the timing of aberrant brain development could be in early gestation.     

Sleep disturbances in children with attention-deficit/hyperactivity disorder

In this article, we advocate the need for better understanding and treatment of children exhibiting inattentive, hyperactive, impulsive behaviors, by in-depth questioning on sleepiness, sleep-disordered breathing or problematic behaviors at bedtime, during the night and upon awakening, as well as night-to-night sleep duration variability. The relationships between sleep and attention-deficit/hyperactivity disorder (ADHD) are complex and are routinely overlooked by practitioners. Motricity and somnolence, the most consistent complaints and objectively measured sleep problems in children with ADHD, may develop as a consequence of multidirectional and multifactorial pathways. Therefore, subjectively perceived or reported restless sleep should be evaluated with specific attention to restless legs syndrome or periodic limb movement disorder, and awakenings should be queried with regard to parasomnias, dyssomnias and sleep-disordered breathing. Sleep hygiene logs detailing sleep onset and offset quantitatively, as well as qualitatively, are required. More studies in children with ADHD are needed to reveal the 24-h phenotype, or its sleep comorbidities.     

Chemosensory processing in children with attention-deficit/hyperactivity disorder

BackgroundIn attention-deficit/hyperactivity disorder (ADHD) not only deficits in dopamine-related cognitive functioning have been found but also a lower dopamine-sensitive olfactory threshold. The aim of the present study was to proof that only olfactory but not trigeminal sensitivity is increased in ADHD. Structural magnetic resonance imaging (MRI) was used to show increased olfactory bulb (OB) volume- a structure which is strongly shaped by olfactory performance through the mechanism of neuroplasticity (e.g. synaptogenesis). To elucidate whether cortical mechanisms are involved in altered olfaction in ADHD, functional MRI (fMRI) was introduced.MethodsA total of 18 boys with ADHD and 17 healthy controls (aged 7–12) were included in the study. Olfactory as well as trigeminal detection thresholds were examined. OB sizes were measured by means of structural MRI and an analysis of effective functional (fMRI) coupling of primary olfactory cortex was conducted. The frontal piriform cortex (fPIR) was chosen as seed region because of its importance in processing both trigeminal and olfactory stimuli as well as having profound influence on inner OB-signaling.ResultsIncreased olfactory sensitivity as well as an increase in OB volume was found in ADHD. There were no group differences in sensitivity towards a trigeminal stimulus. Compared to healthy controls, the fPIR in ADHD was more positively coupled with structures belonging to the salience network during olfactory and, to a lesser extent, during trigeminal stimulation.ConclusionsOlfactory functioning is superior in subjects with ADHD. The observed increase in OB volume may relate to higher olfactory sensitivity in terms of neuroplasticity. During the processing of chemosensory stimuli, the primary olfactory cortex in ADHD is differently coupled to higher cortical structures which might indicate an altered top-down influence on OB structure and function.     

Open-label amantadine in children with attention-deficit/hyperactivity disorder

OBJECTIVES: The purpose of this study was to explore the possible efficacy and tolerability of amantadine in the treatment of attention-deficit/hyperactivity disorder (ADHD) in stimulant-na?ve children. METHODS: Twenty four children (5-13 years old) with Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) ADHD (4 inattentive, 2 hyperactive, and 18 combined type) entered a 6-week open-label treatment with amantadine (50-150 mg) given as a single morning dose. Parent and teacher ADHD rating scales and the parent Child Behavior Checklist (CBCL) were administered at baseline and at week 6. RESULTS: Twenty three subjects completed the 6-week treatment. One child dropped out at week 2 because of persistent headache, and another 12 children reported adverse effects, most commonly transient appetite decrease. The parent ADHD score decreased from mean 41.04 +/- D 6.9 at baseline to 28.9 +/- 8.7 at week 6 (p < 0.001, effect size d = 1.5), and the teacher ADHD score from 35.8 +/- 9.6 to 26.2 +/- 9.5 (p < 0.001, effect size d = 1.0). Response rate (a 25% or greater decline in ADHD score) was 58% based on parents and 46% based on teachers. CONCLUSIONS: These data suggest that amantadine has acceptable acute tolerability at single doses up to 150 mg/day and is possibly efficacious in decreasing ADHD symptoms, although its activity appears to be more modest than that of stimulant medications.     

Hypothalamic-pituitary-adrenal axis function in children with attention-deficit hyperactivity disorder

Examined hypothalamic-pituitary-adrenal axis (HPA axis) function in 30 children with attention-deficit hyperactivity disorder (ADHD) by measuring the diurnal variation and response to the dexamethasone suppression test (DST) of saliva cortisol. Normal diurnal saliva cortisol rhythm was found in only 43.3% of the ADHD children. DST showed suppression in 46.7% of the ADHD children. An abnormal diurnal rhythm and nonsuppression to the DST were more frequent in the severely hyperactive group than in the mildly hyperactive group of children with ADHD. These results suggest abnormalities in HPA axis function in some children with ADHD, especially those exhibiting severe hyperactivity.     

Differentiating bipolar disorder in Turkish prepubertal children with attention-deficit hyperactivity disorder

Background: Attention‐deficit hyperactivity disorder (ADHD) and bipolar disorder (BPD) in children are frequently comorbid conditions. Because the coexistence of ADHD and mania seriously complicates the course of the condition and the treatment of children, diagnosing or missing this comorbidity has important clinical implications. There are very few systematic studies on the subject in the literature and BPD in children is not recognized or studied in most countries other than the USA. We aimed to differentiate Turkish prepubertal children with ADHD from those with comorbid ADHD and BPD and compare their clinical characteristics. Methods: A total of 147 treatment‐ and drug‐naïve children, aged 7 to 13 years, who had been consecutively referred to the ADHD clinic, were evaluated using the Schedule for Affective Disorders and Schizophrenia for School‐age Children–Present and Lifetime version (K–SADS–PL). Parents completed the Child Behavior Checklist (CBCL) 4–18 and the Parent–Young Mania Rating Scale (P–YMRS) prior to the clinical interview. Results: Twelve children (8.2%) had comorbid bipolar disorder (ADHD + BPD). The ADHD + BPD group had significantly higher rates of depressive disorders, oppositional defiant disorder, panic disorder and a family history of bipolar disorder compared with the ADHD group. The ADHD + BPD group had significantly more problems on the CBCL scale (anxiety/depression, social problems, thought problems, aggression, externalization, and total score) and on the P–YMRS (all items except for insight) compared with the ADHD group. Conclusions: We conclude that ADHD + BPD in Turkish children represents a clinical picture different to that of ADHD alone, in which the clinical characteristics resemble those of children reported in the literature. Further long‐term follow‐up studies are needed in larger clinical and community samples.