DAT1 methylation is associated with methylphenidate response on oppositional and hyperactive-impulsive symptoms in children and adolescents with ADHD

Objectives: To examine the association of the DNA methylation of DAT1 and DRD4 gene with methylphenidate (MPH) response in attention deficit hyperactivity disorder (ADHD).

Methods: One hundred and eleven DSM-IV defined ADHD Chinese Han children were recruited. Inattention, hyperactivity–impulsivity and oppositional symptoms were evaluated by the Swanson, Nolan and Pelham–IV–parent rating scale (SNAP-IV-P) at baseline and 6 weeks after MPH treatment. DNA methylation of CpG sites in the promoter sequences of DAT1 and DRD4 was examined for association with treatment response.

Results: Greater improvement on the SNAP-IV-P total score and percentage change from baseline score were both significantly correlated with DAT1 methylation (rho?=?0.222, P?=?.019 and rho?=??0.203, P?=?.032, respectively). A secondary analysis demonstrated that the effect of DAT1 methylation on symptom response was primarily related to the percentage change in oppositional symptoms (rho?=??0.242; P?=?.012), with a smaller significant effect on hyperactivity–impulsivity (rho?=??0.192; P?=?.045). No significant correlation was found between the treatment effect on inattention and DAT1 methylation (rho?=??0.101; P?=?.292). No significant correlation was observed between mean DRD4 methylation and measures of treatment outcome or baseline symptoms.

Conclusions: Our findings provide initial evidence for the involvement of the epigenetic alterations of DAT1 in modulating the response to MPH treatment in ADHD, primarily on oppositional and hyperactive-impulsive symptoms.     

Methylphenidate effects on processing speed in a clinical sample of adults with ADHD and substance use disorder: a pilot study

Background: Substance use disorders (SUDs) are common comorbidities of Attention Deficit Hyperactivity Disorder (ADHD). The most commonly prescribed medication for ADHD is methylphenidate. The clinical response to methylphenidate may be monitored against DSM-5 symptomatology, rating scales or interviews.

Aims: To evaluate the use of perceptual and cognitive processing speed measures to monitor methylphenidate effects in adults with ADHD and SUD.

Methods: A Quick Test of Cognitive Speed (AQT) monitored perceptual and cognitive processing speed in 28 adults with ADHD and SUD on treatment with methylphenidate before and after the morning dose.

Results: Twenty-six patients responded on AQT after the morning dose of methylphenidate. One-way ANOVA indicated significant treatment effects for color, form, and color-form combination naming, but not for shift cost values. Before the morning dose of methylphenidate, 92% were identified by cutoff time criteria for longer-than-normal processing times. After the morning dose of methylphenidate, 65% obtained color and form measures in the normal range for age peers. Only 35% obtained color-form processing measures in the normal range. Inter-individual response variability before medication intake was considerably larger than previously reported in studies of adults with ADHD only.

Conclusion: Proportionally, fewer adults with ADHD and SUD exhibited normalization of processing speed than previously observed for adults with ADHD without SUD. A potential clinical implication of the present study is that the AQT test may be used as a tool for dose-adjustment of central stimulants in the treatment of adults with ADHD and SUD.     

Influence of striatal dopamine transporter availability on the response to methylphenidate in adult patients with ADHD

In this study, we investigated whether availability of striatal dopamine transporter (DAT) may have an influence on the response of adult patients with attention deficit hyperactivity disorder (ADHD) on methylphenidate (MPH). In 18 non–smoking and non–medicated adult patients with ADHD, availability of DAT was measured with [^99mTc] TRODAT–1 SPECT. Then, the patients received methylphenidate (MPH), individually titrated up to 60 mg per day. Ten weeks later, clinical improvement was rated by Clinical Global Impressions scale. In all, 6 patients were classified as non–responders, and 12 responded to MPH. From the non–responders, 5 presented with a DAT availability below that of normal controls of the same age, whereas in the group of responders all patients had elevated DAT availability. There was a significant negative correlation between values for global clinical improvement and striatal DAT availability. In conclusion, ADHD patients with low DAT availability seem not to respond to therapy with MPH.     

The International ADHD in Substance Use Disorders Prevalence (IASP) study: background,methods and study population

Attention deficit/hyperactivity disorder (ADHD) is an increasingly recognized comorbid condition in subjects with substance use disorders (SUDs). This paper describes the methods and study population of the International ADHD in Substance Use Disorders Prevalence (IASP) study. Objectives of the IASP are to determine the prevalence of ADHD in adult treatment seeking patients with SUD in different countries and SUD populations, determine the reliability and validity of the Adult ADHD Self‐report Scale V 1.1 (ASRS) as ADHD screening instrument in SUD populations, investigate the comorbidity profile of SUD patients with and without ADHD, compare risk factors and protective factors in SUD patients with and without a comorbid diagnosis of ADHD, and increase our knowledge about the relationship between ADHD and the onset and course of SUD. In this cross‐sectional, multi‐centre two stage study, subjects were screened for ADHD with the ASRS, diagnosed with the Conner's Adult ADHD Diagnostic Interview for DSM‐IV (CAADID), and evaluated for SUD, major depression, bipolar disorder, anti social personality disorder and borderline personality disorder. Three thousand five hundred and fifty‐eight subjects from 10 countries were included. Of these 40.9% screened positive for ADHD. This is the largest international study on this population evaluating ADHD and comorbid disorders. Copyright © 2013 John Wiley & Sons, Ltd.     

Performance monitoring and response inhibition in anxiety disorders with and without comorbid ADHD

Anxiety disorder (ANX) is characterized by heightened arousal, psychosocial and academic difficulties, and comorbidity with other disorders, in particular, attention-deficit/hyperactivity disorder (ADHD). The heightened arousal contributes to cognitive impairment by adversely affecting executive control of cognition. The nature of the effect on executive control is poorly understood. Research in this area could inform intervention, diagnostic, and etiological research. Our objective was to characterize children with ANX on measures of executive functioning, while controlling for comorbid ADHD. We compared children ages 6-14 with ANX (N=21), ADHD (N=78), ANX+ADHD (N=38), and normal controls (NC; N=40) on the stop task, a measure of performance monitoring and response inhibition. No difference was observed between NC and ANX groups in performance monitoring. Compared to the NC group, the three clinical groups showed inhibition deficits, and both ADHD and ANX+ADHD groups monitored less after responses. ANX was not associated with performance monitoring or inhibition deficits once comorbid ADHD was considered. This emphasizes the importance of controlling for comorbid ADHD in studies of cognition and anxiety.     

Combined methylphenidate and atomoxetine pharmacotherapy in attention deficit hyperactivity disorder

Object?ves. Pharmacological treatment of attention deficit hyperactivity disorder (ADHD) includes stimulant and non-stimulant medications. Our purpose in this study is to investigate efficacy, safety and tolerability of combined methylphenidate and atomoxetine pharmacotherapy. Methods. We included 12 patients of the 824 patients with ADHD using methylphenidate and atomoxetine combined therapy between the years 2010 and 2014. Kiddie-SADS, Turgay DSM-IV Based Child and Adolescent Behavior Disorders Screening and Rating Scale, Child Behavior Checklist, Clinic Global Impression Scale Severity and Impression (CGIS-S-I) scales were used. Results. Patients were between the ages of 7 and 17 years. Before combined pharmacotherapy the CGIS-S score mean was 5.08. Mean CGIS-S score after the combined pharmacotherapy was 3.08 (P = 0.03; –2,980). The most common side effects were irritability (n = 5, 41.6%), appetite reduction (n = 3, 25%), palpitations (n = 2, 16.7%), headache (n = 1, 8.3%). Conclus?ons. Nine of these 12 patients showed significant improvement in their symptoms, combined therapy enhanced the effectiveness of monotherapy.     

Effects of osmotic-release methylphenidate in attention-deficit/hyperactivity disorder as measured by event-related potentials

Aim: Attention‐deficit/hyperactivity disorder (ADHD) is a relatively common central nervous system disorder in school‐age children, which may involve a specific disorder in cognition and/or information processing. Event‐related potentials (ERP) are commonly used as physiological measures of cognitive function as they are easily measured and non‐invasive. Thus, in the present study, we examined the effects of osmotic‐release methylphenidate (MPH) (Concerta), a common treatment for childhood attention‐deficit/hyperactivity disorder (ADHD), in ADHD children as measured by ERP. Methods: Ten ADHD children participated after giving consent. Based on the guidelines for evoked potential measurement, mismatch negativity (MMN) and P300 were obtained by auditory odd‐ball tasks. We measured both MMN and P300 in the drug‐naive condition and after intake of osmotic‐release MPH. Results: The MMN amplitudes after intake of osmotic‐release MPH were significantly greater than those in the drug‐naive situation at Pz and C4. The P300 amplitudes after intake of osmotic‐release MPH were significantly greater than those in the drug‐naive situation at Cz and Pz. Conclusion: MMN and P300 are sensitive tools for measuring the pharmacological effects of osmotic‐release MPH in ADHD children.     

Dopamine transporter gene,response to methylphenidate and cerebral blood flow in attention-deficit/hyperactivity disorder: a pilot study

The homozygosity of the 10-repeat allele at dopamine transporter gene (DAT1) seems to be associated with a poor response to methylphenidate (MPH) in children with attention-deficit/hyperactivity disorder (ADHD). This pilot study aimed to simultaneously assess polymorphisms at DAT1, response to MPH, and neuroimaging. Only ADHD children with at least a moderate response to MPH were included. Significantly higher regional cerebral blood flows assessed by single photon emission computerized tomography (SPECT) were detected in medial frontal and left basal ganglia areas in children with homozygosity for the 10-repeat allele at DAT1 gene (n = 4) than in children without this genotype (n = 4) (P < 0.05). These findings provide a preliminary connection between pharmacogenetics and neurobiological investigations on stimulant treatment of ADHD.     

两种哌甲酯片治疗多动障碍临床对照研究

目的:比较哌甲酯缓释片与速释片治疗男性注意缺陷多动障碍(ADHD)患儿的疗效和安全性。方法:80例患儿随机分为缓释片组41例,速释片组39例;疗程12周。采用Conners父母用症状问卷(PSQ)、Conners多动指数(C IH)及中国儿童韦氏智力测定量表(C-W ISC)于治疗前后进行评定。结果:治疗2周,两组PSQ在多动指数、品行问题、学习问题、冲动-多动4个因子分均较治疗前有显著改善(P<0.01或P<0.05);治疗4周,缓释片组在心身问题和焦虑2个因子分显著降低(P<0.05)。治疗8周,速释片组焦虑因子分显著降低(P<0.05);治疗12周,两组C IH总分均显著下降(P均<0.01)。缓释片组C-W ISC评分、操作分及B、C因子评分均显著高于治疗前(P<0.01或P<0.05);速释片组除C因子分以外,其他各因子分均显著高于治疗前(P<0.01或P<0.05)。两组不良反应比较差异无显著性(P>0.05)。结论:两药疗效相当。缓释片每天1次服药,可增加患儿服药的依从性。     

Molecular genetics and attention in ADHD

A research program at UC Irvine has investigated the molecular genetic basis of ADHD by focusing on one candidate gene (DRD4) and the highly variable 48 bp VNTR polymorphism in exon 3. Initial studies revealed that the 7R variant is over-represented in ADHD samples, and a subsequent study suggested that the 7R allele is associated with clear excesses in behavior but not with some cognitive deficits thought to be core feature of the disorder. The next phase of this research program showed that (1) the common 7R allele was the product of positive selection, (2) other variation in and around the DRD4 gene is in tight linkage disequilibrium with the 7R allele but not the 4R allele, and (3) more rare 7R variants in the ADHD clinical sample than expected. Based on this program of research, we suggest that the 7R VNTR variant is responsible for the observed association of the DRD4 gene with ADHD, and that a challenge for the future is understanding what other genetic and/or environmental factors influence this association and affect clinical outcome of the disorder.     

Neurophysiological actions of methylphenidate in the primary somatosensory cortex

As a catecholamine reuptake blocker, methylphenidate (MPH) enhances noradrenergic transmission and is likely to influence norepinephrine actions in sensory systems. To characterize neurophysiological actions of MPH in the primary somatosensory (SI) cortex, we recorded basal and whisker deflection-evoked discharge of infragranular sensory cortical neurons, before and after intraperitoneal administrations of saline and MPH (5 mg/kg) in halothane-anesthetized rats. MPH had two types of actions on sensory-evoked neuronal responses in the SI cortex, depending on the initial amplitude of the sensory response. When the whisker deflection induced a small excitatory response under control conditions, MPH significantly increased the amplitude of the response by approximately 40%. When the whisker stimulation induced a large excitatory response under control conditions, MPH did not significantly alter the amplitude of the response, but significantly decreased the duration and the peak latency of the response, so that the response was more focused. These neurophysiological actions of MPH may underlie some of the beneficial effects of the drug on sensory processing and attention.     

Stimulant actions in rodents: implications for attention-deficit/hyperactivity disorder treatment and potential substance abuse.

Most evidence supports the continued use of stimulants as the best available pharmacotherapy for the treatment of children with attention-deficit/hyperactivity disorder (ADHD), but little is known about possible enduring behavioral and neuroadaptational consequences of long-term stimulant exposure. Although a variety of preclinical studies, particularly those using methylphenidate (MP), have attempted to address these issues, most of these studies have used procedures that might not adequately simulate clinical treatment conditions, and results have not been entirely consistent. In particular, the rationale for selection of MP doses that simulate clinical exposure has not been well defined. We suggest that the use of more appropriate treatment conditions, including doses that result in plasma drug levels comparable to therapeutic levels, will provide a more accurate model for adequately assessing the therapeutic mechanisms and potential long-term consequences of stimulant psychotherapy in the treatment of ADHD.     

DAT1和DRD4基因启动子区甲基化与注意缺陷多动障碍临床症状的关联研究

目的探索注意缺陷多动障碍(attention deficit hyperactivity disorder,ADHD)患儿多巴胺转运体基因(dopamine transporter gene,DAT1)、多巴胺D4受体基因(dopamine receptor D4 gene,DRD4)启动子区CpG岛甲基化状态与其临床症状严重程度的相关性。方法收集111例ADHD患儿精神类疾病家族史资料,并采用ADHD症状分级父母评定量表(attention deficit hyperactivity disorder rating scale-Ⅳhome version,ADHD-RS-Ⅳ)及自编对立违抗障碍(oppositional defiant disorder,ODD)量表对患者临床症状进行评定。采用亚硫酸氢钠测序法,检测患者外周血的DAT1、DRD4启动子区CpG岛目标片段甲基化状态。结果无抑郁、焦虑和ADHD家族史的患儿DAT1启动子区甲基化水平高于有抑郁、焦虑或ADHD家族史的患儿(P0.05)。DAT1和DRD4甲基化水平在ADHD-RS-Ⅳ总分(≤30分组与30分组)、注意缺陷因子分(≤17分组与17分组)、多动冲动因子分(≤13分组与13分组)低分和高分组的比较中差异均无统计学意义(均P0.05)。ODD量表9分的患儿DAT1甲基化水平较ODD量表得分≥9分的患儿高(P0.05),且患儿DAT1甲基化水平与ODD量表得分呈负相关(r=-2.203,P=0.033)。结论 DAT1启动子区甲基化水平可能影响ADHD患者对立违抗行为的严重程度,且与患者有无抑郁、焦虑和ADHD家族史存在一定关系。     

The effect of methylphenidate treatment on suspiciousness in children with ADHD alone or comorbid with ODD

Objective: To assess the level of the suspiciousness in children with attention deficit/hyperactivity disorder (ADHD) and comorbid oppositional defiant disorder (ODD) in comparison to ADHD alone and the response of suspiciousness symptoms to methylphenidate (MPH) treatment.

Methods: In this open-label comparative study, children with DSM-IV-TR ADHD, aged 8–18 years, with (N?=?30) or without (N?=?30) ODD received MPH treatment for 12 weeks. The severity of ODD symptoms was assessed by the Kiddie–Schedule for Affective Disorders and Schizophrenia. The severity of ADHD symptoms was assessed by the ADHD-Rating-Scale-IV and suspiciousness was assessed at baseline and at endpoint by a scale designed especially for assessment of suspiciousness and named Suspiciousness Rating Scale (SRS).

Results: Significant reductions in SRS scores were detected in both groups following MPH treatment (before and after: p?= .0012 and p?=?.0273, respectively). Only in the ADHD/ODD group a significant correlation was found between the rate of improvement in ADHD, as assessed by the ADHD–RS, and the reduction in suspiciousness, as assessed by the SRS (Spearman r?=?0.48, p?= .0066).

Conclusions: In addition to the beneficial effect of MPH treatment on ADHD and ODD symptoms it also diminishes suspiciousness. However, due to the small sample size further studies are needed to confirm the present results.     

The structure of adult ADHD

Although DSM‐5 stipulates that symptoms of attention‐deficit hyperactivity disorder (ADHD) are the same for adults as children, clinical observations suggest that adults have more diverse deficits than children in higher‐level executive functioning and emotional control. Previous psychometric analyses to evaluate these observations have been limited in ways addressed in the current study, which analyzes the structure of an expanded set of adult ADHD symptoms in three pooled US samples: a national household sample, a sample of health plan members, and a sample of adults referred for evaluation at an adult ADHD clinic. Exploratory factor analysis found four factors representing executive dysfunction/inattention (including, but not limited to, all the DSM‐5 inattentive symptoms, with non‐DSM symptoms having factor loadings comparable to those of DSM symptoms), hyperactivity, impulsivity, and emotional dyscontrol. Empirically‐derived multivariate symptom profiles were broadly consistent with the DSM‐5 inattentive‐only, hyperactive/impulsive‐only, and combined presentations, but with inattention including executive dysfunction/inattention and hyperactivity‐only limited to hyperactivity without high symptoms of impulsivity. These results show that executive dysfunction is as central as DSM‐5 symptoms to adult ADHD, while emotional dyscontrol is more distinct but nonetheless part of the combined presentation of adult ADHD.     

Driving-related risks and impact of methylphenidate treatment on driving in adults with attention-deficit/hyperactivity disorder (ADHD)

Summary. This study assesses driving behaviour and history of driving outcomes through a semi-structured interview in 27 clinically referred German adults with ADHD and 27 age-, gender- and education-matched non-ADHD controls. In nineteen of the ADHD-subjects a test battery of driving-related cognitive measures was performed (ART 2020) and re-assessed after at least six weeks of treatment with methylphenidate (n = 9) or after a six-week medication free period (n = 10). ADHD-subjects drove significantly more kilometres per year, were more often registered by traffic authorities and fined more frequently, were involved in more accidents and described their driving style as more insecure and hectic than controls. A high-risk driving group was delineated with 3–6 accidents per ADHD-subject. All results were controlled for intercorrelations with driving experience. Methylphenidate treatment resulted in improved information processing, e.g., better visu-motor coordination under high-stress conditions, improved visual orientation and sustained visual attention compared to baseline and our untreated control group. Correspondence: Esther Sobanski, Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, J 5, 68159 Mannheim, Germany