The relationship between regional cerebral blood flow and response to methylphenidate in children with attention-deficit hyperactivity disorder: comparison between non-responders to methylphenidate and responders

In a sample of children with attention-deficit hyperactivity disorder (ADHD), a voxel based investigation of regional cerebral blood flow (rCBF) during resting state was conducted to identify functional differences between non-responders to methylphenidate (MPH) and responders. Thirty-four children with ADHD were examined by technetium-99m-hexamethylporphylenamine oxime (HMPAO) SPECT. According to clinical response after 8 weeks of treatment with MPH, they were classified as non-responders to MPH and responders. Using SPM analysis, we compared the SPECT images of non-responders to MPH with those of responders. Non-responders to MPH had higher rCBF in the left anterior cingulate cortex, the left claustrum, the right anterior cingulate cortex, and the right putamen relative to responders. In addition, lower rCBF was found in the right superior parietal lobule in non-responders to MPH relative to responders. Further stepwise discriminant analysis revealed that 88.2% could be correctly classified as either non-responders to MPH or responders when considering the extracted rCBF values in the left anterior cingulate cortex, the left claustrum, and the right superior parietal lobule. The current findings suggest that non-responders to MPH may have different patterns of rCBF in brain regions, which have been known as a part of frontal-striatal circuitry and posterior attentional system, respectively.     

Regional cerebral blood flow in children with attention deficit hyperactivity disorder: comparison before and after methylphenidate treatment

Differences in brain activity of children with attention deficit hyperactivity disorder (ADHD) have been compared to normal healthy controls, suggesting neural correlates of cognitive/behavioral symptoms. Symptoms are improved with methylphenidate treatment but limited sources can be cited to show how brain activity in ADHD is altered after pharmacologic treatment. We investigated how long-term oral medication of methylphenidate affects the resting regional cerebral blood flow (rCBF) in ADHD children, using single photon emission computerized tomography (SPECT). rCBF was decreased in the orbitofrontal cortex and middle temporal gyrus in the right hemisphere whereas it was increased in the dorsomedial prefrontal and somatosensory area bilaterally in drug-naive ADHD children compared to control child subjects. After treatment with methylphenidate, the extent of hyperperfusion in the somatosensory area was reduced and significant reduction of rCBF was found in the right striatum for the first time. Methylphenidate treatment also resulted in rCBF increase in superior prefrontal and reduction in ventral higher visual areas bilaterally. The results indicated that improving ADHD symptom after methylphenidate is associated with normalization of abnormally reduced orbitofrontal activity and abnormally increased somatosensory cortical activity. These changes were accompanied with reduced striatum activity lower than that of normal controls. These changes might be associated with improving ADHD to control attention and motor response to irrelevant environmental stimuli after methylphenidate treatment.     

Rapid improvement in academic grades following methylphenidate treatment in attention-deficit hyperactivity disorder

In the present study a 16 week comparison study was conducted of behavioral, cognitive and educational measures in school-age Taiwanese children with attention-deficit hyperactivity disorder (ADHD) receiving open-label methylphenidate (MPH). Subjects include 14 male and five female ADHD children. They received MPH twice per day continuously for 16 weeks. Measures of behavior, cognitive function (Wisconsin Card Sorting Test, Tower of London and Continuous Performance Test), Chinese and arithmetic learning achievement were compared with those of their baseline condition. After MPH, 68-78% of children showed improving behavior in classroom and at home. Among the neuropsychological tests, only the percentage of preservative error was improved (P = 0.022). Approximately 61-66% of children had improvement in academic learning (P = 0.013 for Chinese, 0.004 for arithmetic). The MPH treatment demonstrated improvement in domains of classroom/home behaviors and academic performance, but showed minimal change on neuropsychological functioning in Taiwanese ADHD children. The finding of academic gain was unexpected, which might be due to the greater interest in achievement and better compliance to cultural expectations by Taiwanese versus Western students, which translated into more rapid improvement in academic performance.     

Executive functions and methylphenidate response in subtypes of attention-deficit/hyperactivity disorder.

BACKGROUND: Oculomotor tasks are a well-established means of studying executive functions and frontal-striatal functioning in both nonhuman primates and humans. Attention-deficit/hyperactivity disorder (ADHD) is thought to implicate frontal-striatal circuitry. We used oculomotor tests to investigate executive functions and methylphenidate response in two subtypes of ADHD. METHODS: Subjects were boys, aged 11.5-14 years, with ADHD-combined (n = 10), ADHD-inattentive (n = 12), and control subjects (n = 10). Executive functions assessed were motor planning (tapped with predictive saccades), response inhibition (antisaccades), and task switching (saccades-antisaccades mixed). RESULTS: The ADHD-combined boys were impaired relative to control subjects in motor planning (p < .003) and response inhibition (p < .007) but not in task switching (p > .92). They were also significantly impaired relative to ADHD-inattentive boys, making fewer predictive saccades (p < .03) and having more subjects with antisaccade performance in the impaired range (p < .04). Methylphenidate significantly improved motor planning and response inhibition in both subtypes. CONCLUSIONS: ADHD-combined but not ADHD-inattentive boys showed impairments on motor planning and response inhibition. These deficits might be mediated by brain structures implicated specifically in the hyperactive/impulsive symptoms. Methylphenidate improved oculomotor performance in both subtypes; thus, it was effective even when initial performance was not impaired.     

In vivo neuroreceptor imaging in attention-deficit/hyperactivity disorder: a focus on the dopamine transporter.

There is converging evidence of the role of catecholamine dysregulation in the underlying pathophysiology of attention-deficit/hyperactivity disorder (ADHD). The dopamine transporter (DAT) is known to be a key regulator of dopamine, and recent genetic, treatment, and imaging studies have highlighted the role of DAT in ADHD. There is an emerging literature on in vivo neuroreceptor imaging of DAT in ADHD and control subjects reported by a number of groups internationally. A comprehensive review of existing imaging studies of DAT binding in ADHD shows that six of eight independent studies by six different groups have reported increased DAT binding in (mostly) treatment-na?ve children and adults with ADHD. Although there is fair agreement regarding the presence and direction of abnormal DAT binding, there remains disagreement as to the magnitude of the finding and the importance of many potentially confounding variables, including clinical characteristics and imaging methodology. Three studies by three different groups have reported decreased DAT binding after methylphenidate treatment. Interpretation of the latter finding awaits clarification of the issue of timing of drug administration and imaging to disentangle receptor occupancy from downregulation.     

The dopamine transporter gene and the impulsivity phenotype in attention deficit hyperactivity disorder: a case-control association study in a Korean sample

The dopamine transporter gene (DAT1) has been extensively studied as one of the candidate genes in attention-deficit/hyperactivity disorder (ADHD). Several studies have reported on the association between the DAT1 10-repeat allele and cognitive variables in ADHD. However, few studies have been designed to ascertain the association between DAT1 genotypes other than the 10-repeat allele and cognitive endophenotypes in ADHD. The aim of this study was to examine the relationship between the DAT1 genotypes and the candidate endophenotypes, inattention and impulsivity symptoms, as measured by the continuous performance test (CPT), in a Korean sample of 85 children diagnosed with DSM-IV ADHD. Compared to the normal control group, the frequencies of the 9/10 genotype were significantly higher in the ADHD probands (χ² = 13.45, p = 0.02, OR = 4.12, 95% CI: 2.21–12.34) and parents of probands (χ² = 11.60, p = 0.03). The 9-repeat allele frequencies were significantly higher in the ADHD probands (χ² = 11.55, p = 0.03, OR = 4.43, 95% CI: 1.55–11.78) and parents of probands (χ² = 12.70, p = 0.03) than the normal control group. Compared to the ADHD probands without the 9-repeat allele (n = 74), the mean T-score, with regard to the commission errors of the CPT, was significantly higher (p < 0.05) in the ADHD probands with the 9-repeat allele (n = 11). Compared to the ADHD probands with other DAT1 genotypes, the mean T-score, with respect to the commission errors of the CPT, was significantly higher in the ADHD probands with the 9/10 genotype (p < 0.05). The results of this study suggest the possibility of an association between the DAT1 9-repeat allele and the impulsivity phenotype of ADHD.     

A randomized, placebo-controlled trial of OROS methylphenidate in adults with attention-deficit/hyperactivity disorder.

BACKGROUND: The objective of this study was to evaluate the safety and efficacy of once-daily OROS methylphenidate (MPH) in the treatment of adults with DSM-IV attention-deficit/hyperactivity disorder (ADHD). METHODS: We conducted a randomized, 6-week, placebo-controlled, parallel-design study of OROS MPH in 141 adult subjects with DSM-IV ADHD, using standardized instruments for diagnosis. OROS MPH or placebo was initiated at 36 mg/day and titrated to optimal response, depending on efficacy and tolerability, up to 1.3 mg/kg/day. RESULTS: Treatment with OROS MPH was associated with clinically and statistically significant reductions in DSM-IV symptoms of inattention and hyperactivity/impulsivity relative to subjects treated with placebo. At endpoint, 66% of subjects (n = 44) receiving OROS MPH and 39% of subjects (n = 29) [corrected] receiving placebo attained our a priori definition of response of much or very much improved on the Clinical Global Impression-Improvement scale plus a >30% reduction in Adult ADHD Investigator System Report Scale score. OROS MPH was associated with small but statistically significant increases in systolic blood pressure (3.5 +/- 11.8 mm Hg), diastolic blood pressure (4.0 +/- 8.5 mm Hg), and heart rate (4.5 +/- 10.5 bpm). CONCLUSIONS: These results show that treatment with OROS MPH in daily doses of up to 1.3 mg/kg/day was effective in the treatment of adults with ADHD. Because of the potential for increases in blood pressure and heart rate, subjects receiving treatment with MPH should be monitored for changes in blood pressure parameters during treatment.     

A randomised,placebo-controlled, 24-week,study of low-dose extended-release methylphenidate in adults with attention-deficit/hyperactivity disorder

Introduction

Attention-deficit/hyperactivity disorder (ADHD) affects many adults who had ADHD in childhood. Although stimulants and methylphenidate in particular are a common off-label treatment for adult patients with ADHD in European countries, little is known about their long-term efficacy and safety.

Methods

A randomized, 24-week double-blind, placebo-controlled, parallel-design study of extended-release methylphenidate (MPH ER) in 359 adult individuals with ADHD according to DSM-IV. Standardized instruments were used for diagnosis. Treatment was started with MPH ER doses of 10 mg/day and titrated up to 60 mg/day, depending on individual efficacy and tolerability. Mean daily MPH SR dose was 0.55 mg/kg.

Results

Treatment with MPH ER resulted in clinical and statistically significant reductions of ADHD symptoms rated with the Wender-Reimherr adult attention deficit disorder scale (WRAADDS) and symptoms of inattention and hyperactivity/impulsivity according to DSM-IV, respectively. Improvements were maintained significant versus placebo up to week 24 of treatment. At endpoint, 61% of the subjects receiving MPH ER were rated as responders according to the a priori definition of response of more than 30% reduction of the WRAADDS score, compared to 42% in the placebo group. The second defined response criterion of much or very much improved on the clinical global impression scale (CGI) was fulfilled by 55% of subjects receiving MPH ER and 37% of subjects receiving placebo. MPH ER treatment was associated with a statistically significant increase of pulse at week 4 (72 bpm at baseline, 77 bpm at week 4). There were no significant differences of heart rate or blood pressure between treatment and placebo groups at any time point.

Discussion

MPH ER treatment in low to moderate doses was effective and safe in the treatment of ADHD in adults. Efficacy measures were clinical and statistically significant and robustly sustained during the 24-week observation period. In this study, no clinical significant effects on blood pressure but a transient increase of the heart rate were found. The interpretation of the results is limited by the low dose-range used in this study, the high drop-out rate and placebo-response which might have affected the therapeutic effect size.

     

Genome-wide association study of blood pressure response to methylphenidate treatment of attention-deficit/hyperactivity disorder

Objective

We conducted a genome-wide association study of blood pressure in an open-label study of the methylphenidate transdermal system (MTS) for the treatment of attention-deficit/hyperactivity disorder (ADHD).

Method

Genotyping was conducted with the Affymetrix Genome-Wide Human SNP Array 6.0. Multivariate association analyses were conducted using the software package PLINK. After data cleaning and quality control we tested 316,934 SNPs in 140 children with ADHD.

Results

We observed no genome-wide statistically significant findings, but a SNP in a K⁺-dependent Na⁺/Ca²⁺ exchanger expressed in vascular smooth muscle (SLC24A3) was included in our top associations at p < 1E-04. Genetic enrichment analyses of genes with ≥ 1 SNP significant at p < 0.01, implicated several functional categories (FERM domain, p = 5.0E-07; immunoglobulin domain, p = 8.1E-06; the transmembrane region, p = 4.4E-05; channel activity, p = 2.0E-04; and type-III fibronectins, p = 2.7E-05) harboring genes previously associated with related cardiovascular phenotypes.

Conclusions

The hypothesis generating results from this study suggests that polymorphisms in several genes consistently associated with cardiovascular diseases may impact changes in blood pressure observed with methylphenidate pharmacotherapy in children with ADHD.     

多巴胺转运体基因与注意缺损多动障碍

目的　探讨注意缺损多动障碍（ＡＤＨＤ） 与多巴胺转运体（ＤＡＴ１） 基因间的关系。方法　分别采用基于单体型和基于基因型的单体型相对风险分析方法,在上海地区汉族人群中对ＡＤＨＤ 与ＤＡＴ１ 基因微卫星多态性进行遗传关联分析。结果　①上海地区汉族人中,ＤＡＴ１ 基因多态以４８０ ｂｐ 重复片段为主,其基因频率为９２％ 。②以父母双亲为对照,经ＧＨＲＲ 和ＨＨＲＲ 分析,ＤＡＴ１ 基因与ＡＤＨＤ 均无关联。结论　上海地区汉族人群中ＤＡＴ１ 基因多态与ＡＤＨＤ 无关。     

A large, double-blind, randomized clinical trial of methylphenidate in the treatment of adults with attention-deficit/hyperactivity disorder.

BACKGROUND: The few controlled studies of methylphenidate (MPH) in adults with attention deficit/hyperactivity disorder (ADHD) have reported equivocal results. A previous, pilot study by our group suggested that these results were due to inadequate dosing. METHOD: We conducted a randomized, 6-week, placebo-controlled, parallel study of MPH in 146 adult patients with DSM-IV ADHD using standardized instruments for diagnosis, separate assessments of ADHD, depressive and anxiety symptoms, and a robust average oral daily dose of 1.1 mg/kg/day. RESULTS: We found a marked therapeutic response for the MPH treatment of ADHD symptoms that exceeded the placebo response (76% vs. 19%). Treatment was safe and well tolerated. Response to MPH was independent of socioeconomic status, gender, and lifetime history of psychiatric comorbidity. CONCLUSIONS: These results confirm that robust doses of MPH are effective in the treatment of adult ADHD.     

Molecular genetic contribution to the developmental course of attention-deficit hyperactivity disorder

Objective  The developmental trajectory of attention-deficit hyperactivity disorder (ADHD) is variable. Utilizing a longitudinally assessed sample, we investigated the contribution of susceptibility gene variants, previously implicated through pooled or meta-analyses, to the developmental course of Attention-Deficit Hyperactivity Disorder over time. Methods  151 children (aged 6–12) who met diagnostic criteria for ADHD were assessed using research diagnostic interviews during childhood and 5 years later in adolescence. Severity was defined as total number of ADHD symptoms at baseline and reassessment. Association with variants at DRD4, DRD5, and the dopamine transporter gene, DAT was analyzed using linear regression. Results  As expected, affected individuals showed a decline in ADHD severity over time. The DRD4 48 bp VNTR 7-repeat and DRD5 CA(n) microsatellite marker 148 bp risk alleles were associated with persistent ADHD. Those possessing the DRD4 7 repeat risk allele showed less of a decline in severity at reassessment than those without the risk allele. Conclusions  Those carrying the DRD4 7 risk allele showed greater symptom severity at follow-up and less ADHD reduction over time. These findings support the hypothesis that some susceptibility genes for ADHD also influence its developmental course.     

Brain biochemical effects of methylphenidate treatment using proton magnetic spectroscopy in youth with attention-deficit hyperactivity disorder: a controlled pilot study

Introduction: This study conducted spectroscopic analyses using proton (1H) Magnetic Resonance Spectroscopy (at 4 Tesla) in a sample of adolescents with Attention Deficit Hyperactivity Disorder (ADHD), before and after treatment with extended release methylphenidate (OROS MPH), as compared to a sample of healthy comparators. Aims: The main aim of this study is to use 1H MRS to measure differences in brain biochemistry between adolescents with and without ADHD, and to assess changes in cerebral biochemistry, before and after stimulant treatment in ADHD youth. Results: Subjects with ADHD were medically healthy adolescents treated in an open label fashion with OROS MPH (mean dose: 54 mg/day; 0.90 mg/kg/day). Subjects with ADHD were scanned before and after OROS MPH treatment. Healthy comparators were scanned once. Magnetic resonance (MR) spectroscopy studies were performed on a 4.0 T Varian Unity/Inova MR scanner; proton spectra were acquired from the Anterior Cingulate Cortex (ACC). Data were analyzed using MANOVA and repeated measurement ANOVA. Higher metabolite ratios (Glutamate/myo‐inositol, Glutamine/myo‐inositol, Glutamate + Glutamine/myo‐inositol) were observed in the ACC in untreated ADHD subjects as compared to controls, and to treated ADHD youth; these group differences did not reach the a priori threshold for statistical significance. Conclusions: These preliminary findings suggest the presence of glutamatergic abnormalities in adolescents with ADHD, which may normalize with MPH treatment. Larger sample, controlled studies are needed to confirm these preliminary findings.     

Effect of methylphenidate on executive functioning in adults with attention-deficit/hyperactivity disorder: normalization of behavior but not related brain activity.

BACKGROUND: We examined the effect of prolonged methylphenidate (MPH) treatment on the functional neuroanatomy of executive functioning in adult men with attention-deficit/hyperactivity disorder (ADHD). METHODS: Positron emission tomography with [(15)O] water measured alterations of regional cerebral blood flow (rCBF) during the Paced Auditory Serial Addition Task and a control task in 10 ADHD and 11 normal control men. Attention-deficit/hyperactivity disorder men were imaged unmedicated and after a clinically optimal dose of MPH for 3 weeks. RESULTS: Methylphenidate improved ADHD task performance, reduced rCBF in the prefrontal cortex (PFC), and increased rCBF in the right thalamus and precentral gyrus. Comparisons between the ADHD and normal control groups showed that normal control participants exhibited greater anterior cingulate cortex and temporal gyrus rCBF than ADHD participants under both conditions. Executive functioning was associated with greater subcortical (basal ganglia and cerebellar vermis) activation in the ADHD than normal control group under both conditions. CONCLUSIONS: Methylphenidate does not normalize task-related activity in ADHD. Task-related rCBF decreases in the PFC may be due to improved filtering out of task-irrelevant stimuli by way of MPH-mediated dopamine release in the PFC.     

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.     

Autonomic hypoactivity in boys with attention-deficit/hyperactivity disorder and the influence of methylphenidate

Objectives. This study investigates an overall autonomic hypoactivity reflecting hypoarousal as important aetiological factor in ADHD at baseline during rest and in response towards stimuli. In addition, effects of methylphenidate (MPH) are examined. We further assessed whether this hypoarousal is a stable characteristic or ameliorated by arousing emotional stimuli. Methods. Boys with ADHD were examined with (n = 35) or without MPH (n = 45) and compared with healthy boys (n = 22) regarding skin conductance level (SCL) during rest and skin conductance responses (SCRs) as well as valence and arousal ratings in response to positive, neutral, and negative pictures. Results. ADHD children without MPH were characterized by reduced baseline SCL and overall reduced SCRs. ADHD children with MPH never differed from control children. All groups displayed normal valence and arousal ratings of the stimuli and enhanced SCRs to emotional in comparison to neutral pictures. Conclusions. This is the first study to unravel (1) a general autonomic hypoactivity in ADHD children at baseline and in response to low arousing neutral and highly arousing emotional stimuli, and (2) hints that MPH normalizes this hypoactivity. Results contribute to the understanding of ADHD aetiology and MPH functionality, and are consistent with the cognitive-energetic model of ADHD.     

Dissecting the attention deficit hyperactivity disorder (ADHD) phenotype: sustained attention, response variability and spatial attentional asymmetries in relation to dopamine transporter (DAT1) genotype

ADHD is a childhood-onset behavioural disorder with a heterogeneous profile of neuropsychological impairment. Neuropsychological heterogeneity may, in part, reflect underlying genetic differences. Here we examined sustained attention, response variability and spatial attentional asymmetries in a sample of children and adolescents with ADHD (n=22) in relation to dopamine transporter genotype (DAT1) and also controls (n=20). Participants performed the sustained attention to response task (SART) (testing sustained attention and response variability) and the greyscales task (a perceptual measure of attentional bias). The latter has previously been shown to yield a robust leftward attentional asymmetry in healthy subjects. The 10-repeat allele of the DAT1 gene has been associated with ADHD in a number of studies and appears to have biological significance. The ADHD group was sub-divided into those individuals with two copies of the "high-risk" 10-repeat allele (high-risk DAT1) versus those with one or no copies of this allele (low-risk DAT1). The high-risk DAT1 ADHD group displayed greater response variability on the SART than either the low-risk DAT1 group or healthy controls, whereas the latter two groups did not differ. Further, the high-risk DAT1 group showed an attenuated spatial asymmetry, relative to the low-risk DAT1 ADHD group, who showed the typical leftward attentional asymmetry. Our results suggest that the 10-repeat DAT1 allele may mediate neuropsychological impairment in ADHD. The application of molecular genetics may help to define neuropsychological impaired subgroups of ADHD.