Atomoxetine improved response inhibition in adults with attention deficit/hyperactivity disorder.

BACKGROUND: Atomoxetine, a highly selective noradrenaline reuptake inhibitor (SNRI), shows efficacy in the treatment of attention-deficit/hyperactivity disorder (ADHD). Compared with psychostimulants, atomoxetine has a distinct mode of brain action and potentially lower addictive potential. Studies have yet to assess whether atomoxetine improves cognition following a single oral dose in ADHD. METHODS: Twenty-two adults with DSM-IV ADHD were administered a single oral dose of atomoxetine (60 mg) in a placebo-controlled double-blind crossover design. Cognitive effects were assessed using stop-signal, sustained attention, spatial working memory, and set-shifting paradigms. Normative cognitive data from 20 healthy volunteers were collected for comparison. RESULTS: The ADHD patients under placebo conditions showed response inhibition and working memory deficits compared with healthy volunteers. Atomoxetine treatment in the ADHD patients was associated with shorter stop-signal reaction times and lower numbers of commission errors on the sustained attention task. CONCLUSIONS: Atomoxetine improved inhibitory control, most likely via noradrenergically mediated augmentation of prefrontal cortex function. These results have implications for understanding the mechanisms by which atomoxetine exerts beneficial clinical effects and suggest novel treatment directions for other disorders of impulsivity.     

Methylphenidate improves visual-spatial memory in children with attention-deficit/hyperactivity disorder

OBJECTIVE: To investigate the effect of methylphenidate (MPH) on visual-spatial memory, as measured by subtests of the Cambridge Neuropsychological Testing Automated Battery (CANTAB), in children with attention-deficit/hyperactivity disorder (ADHD). Visual-spatial memory is a core component of working memory that has been shown to be impaired in ADHD, irrespective of comorbid reading and/or language problems. METHOD: A clinic-referred sample of school-age children with a confirmed DSM-IV diagnosis of ADHD (n = 26) completed tests of visual-spatial memory, planning ability, and recognition memory in an acute, randomized, placebo-controlled, crossover trial with three single fixed doses of MPH. MPH effects on right-handed and left-handed motor control were also assessed. RESULTS: MPH significantly improved performance on a self-ordered, updating visual-spatial working memory task and on maintenance of visual-spatial information but had no effects on measures of visual-spatial planning ability or recognition memory. Also, MPH significantly improved left-handed motor control. CONCLUSIONS: Beneficial effects of MPH on visual-spatial processing in ADHD are selective and restricted to visual-spatial memory.     

Cognitive control in adults with attention-deficit/hyperactivity disorder

The objective of the present study was to investigate the ability of adults with Attention-Deficit/Hyperactivity Disorder (ADHD) to direct their attention and exert cognitive control in a forced instruction dichotic listening (DL) task. The performance of 29 adults with ADHD was compared with 58 matched controls from the Bergen Dichotic Listening Database (N > 1500). Participants in the Bergen DL task listen to and report from conflicting consonant-vowel combinations (two different syllables presented simultaneously, one to each ear). They are asked to report the syllable they hear (non-forced condition), or to focus and report either the right- or left-ear syllable (forced-right and forced-left condition). This procedure is presumed to tap distinct cognitive processes: perception (non-forced condition), orienting of attention (forced-right condition), and cognitive control (forced-left condition). Adults with ADHD did not show significant impairment in the conditions tapping perception and attention orientation, but were significantly impaired in their ability to report the left-ear syllable during the forced-left instruction condition, whereas the control group showed the expected left-ear advantage in this condition. This supports the hypothesis of a deficit in cognitive control in the ADHD group, presumably mediated by a deficit in a prefrontal neuronal circuitry. Our results may have implications for psychosocial adjustment for persons with ADHD in educational and work environments.     

A cardiopulmonary study of lisdexamfetamine in adults with attention-deficit/hyperactivity disorder

Abstract

Objectives. Due to concerns about the safety of stimulants for ADHD, novel assessments of the cardiopulmonary impact of these agents are needed. Methods. An open design of lisdexamfetamine (LDX) in 15 adults with DSM-IV ADHD. Following a psychiatric evaluation and medical history, subjects underwent echocardiography (TTE) and cardiopulmonary exercise testing (CPET). LDX was titrated to 70 mg daily over 6 weeks, followed by monthly visits to 6 months. Change in TTE and CPET measures were examined following up to 6 months of LDX. Results. At endpoint, there were no significant alterations in indices of cardiac systolic performance, or in metabolic and ventilatory variables at maximum exertion (P values >0.05). We found significant mean changes in resting LV systolic dimension and Doppler diastolic indices. Change in heart rate recovery at 1 min met statistical significance (P = 0.05). Conclusions. We did not detect clinically meaningful changes in cardiac structure and function or in metabolic and ventilatory variables at maximum exertion in ADHD adults receiving open LDX. The clinical significance of changes in resting LV dimension and indices of diastolic function are not in the direction of cardiomyopathy. Future large sample controlled study can examine these findings, as well as stimulants’ impact on heart rate recovery.     

The cognitive neuroscience of response inhibition: relevance for genetic research in attention-deficit/hyperactivity disorder.

Psychological functions that are behaviorally and neurally well specified may serve as endophenotypes for attention-deficit/hyperactivity disorder (ADHD) research. Such endophenotypes, which lie between genes and symptoms, may relate more directly to relevant genetic variability than does the clinical ADHD syndrome itself. Here we review evidence in favor of response inhibition as an endophenotype for ADHD research. We show that response inhibition--operationalized by Go/NoGo or Stop-signal tasks--requires the prefrontal cortex (PFC), in particular the right inferior frontal cortex (IFC); that patients with ADHD have significant response inhibition deficits and show altered functional activation and gray matter volumes in right IFC; and that a number of studies indicate that response inhibition performance is heritable. Additionally, we review evidence concerning the role of the basal ganglia in response inhibition, as well as the role of neuromodulatory systems. All things considered, a combined right IFC structure/function/response inhibition phenotype is a particularly good candidate for future heritability and association studies. Moreover, a dissection of response inhibition into more basic components such as rule maintenance, vigilance, and target detection may provide yet better targets for association with genes for neuromodulation and brain development.     

Modafinil improves cognition and response inhibition in adult attention-deficit/hyperactivity disorder.

BACKGROUND: Modafinil, a novel cognitive enhancer, has a clinical profile similar to conventional stimulants such as methylphenidate, despite a seemingly different mechanism of action. Modafinil selectively improves neuropsychological task performance in healthy volunteers, possibly through improved inhibitory control. We examined whether modafinil induced similar improvements in adults with attention-deficit/hyperactivity disorder. METHODS: Twenty patients with a DSM-IV diagnosis of attention-deficit/hyperactivity disorder were entered into a double-blind, randomized, placebo-controlled crossover study using a single 200 mg dose of modafinil. RESULTS: Modafinil produced a similar pattern of cognitive enhancement to that observed in healthy adults, with improvements on tests of short-term memory span, visual memory, spatial planning, and stop-signal motor inhibition. On several measures, increased accuracy was accompanied by slowed response latency. This alteration in the speed-accuracy trade-off may indicate that modafinil increases the ability to "reflect" on problems coupled with decreased impulsive responding. Improvements were also seen in sustained attention, which was unaffected in healthy subjects. CONCLUSIONS: If these benefits are shown to be maintained with chronic administration, modafinil may have potential as an important therapy for attention-deficit/hyperactivity disorder with a similar effect to stimulants such as methylphenidate in improving stop-signal response inhibition but without the side effects commonly experienced with amphetamine-like drugs.     

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.     

Functional neuroanatomy of working memory in adults with attention-deficit/hyperactivity disorder.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) in adults is an increasingly recognized psychiatric disorder, linked with impairments in numerous life domains and with neurocognitive dysfunctions. However, the neural substrate of cognitive functioning in adults with this disorder has been relatively unexamined. The objective of this study was to examine neural functioning in ADHD adults during performance on a verbal working memory task. METHODS: A sample of unmedicated adults with ADHD (n = 20) and control subjects (n = 20) performed a 2-back task of working memory, and the blood oxygenation level dependent (BOLD) functional magnetic resonance imaging (fMRI) response was used as a measure of neural activity during working memory performance. RESULTS: Though working memory performance did not differ significantly between ADHD adults and control subjects, ADHD adults showed significantly decreased activity in cerebellar and occipital regions and a trend toward decreased activation in an a priori predicted region of the prefrontal cortex. CONCLUSIONS: ADHD adults showed altered patterns of neural activity despite comparable performance on a verbal working memory task. These findings suggest that the cerebellum is involved in the pathophysiology of at least some cognitive deficits associated with ADHD and emphasize the need for additional research aimed at elucidating the role of the cerebellum in ADHD symptomatology.     

Executive and intellectual functions in attention-deficit/hyperactivity disorder with and without comorbidity

Background: Recent neuropsychological theories have targeted deficient executive functions (EF) as the main characteristic of Attention Deficit Hyperactivity Disorder (ADHD), but the nature of the neuropsychological deficits remains elusive and findings are heterogeneous. In particular, it is still unclear whether ADHD subtypes and comorbidity affect intellectual and executive functioning, because large variability has been found in different patient populations. Furthermore, the role of IQ in EF deficits in individuals with ADHD has been debated. Methods: The aim of the present research was to study in detail the relationship between EF, ADHD subtypes, and comorbid diagnosis by taking into account the potential role of IQ. For this purpose, 23 children (aged from 5 to 16 years; 20 males and 3 females) with a diagnosis of ADHD were selected. Results: Data show no differences between children with different subtypes of ADHD on measures of EF, but they evidence differences on EF measures in children with different comorbidities (internalizing versus externalizing disorder). Namely, compared to the internalizing disorders group, the children with externalizing disorders obtained significantly lower scores on different measures of EF (i.e., verbal working memory and categorical fluency), but these differences were strictly dependent on IQ level. Conclusions: Comorbidity patterns, rather than ADHD subtypes, appear to be more valid for defining the neuropsychological features of the ADHD endophenotype. Moreover, general intelligence seems to play a substantial role in the cognitive processes underling the disorder, especially in relation to externalizing aspects.     

Methylphenidate effects on task-switching performance in attention-deficit/hyperactivity disorder.

OBJECTIVE: To examine the specificity of methylphenidate effects on the processes that support the ability to rapidly and accurately coordinate the performance of multiple tasks in children with attention-deficit hyperactivity disorder (ADHD). METHOD: Twenty children with ADHD performed the task-switching paradigm while on and off medication. The paradigm involves switching between two different tasks, discriminating the value of a number presented on a computer screen and deciding how many numbers were present on the screen. The children also performed single-task control conditions. RESULTS: Analyses of variance indicated the medication selectively enhanced the children's ability to rapidly and accurately switch between tasks and to focus attention on the currently relevant response set. CONCLUSIONS: This study helps to elucidate the nature of methylphenidate effects on the cognitive processes which support the ability to coordinate the performance of multiple tasks. Medication appears to selectively enhance inhibitory processes which support task-switching.     

Association between response inhibition and working memory in adult ADHD: a link to right frontal cortex pathology?

BACKGROUND: We sought to assess the relationship between response inhibition and working memory in adult patients with attention-deficit/hyperactivity disorder (ADHD) and neurosurgical patients with frontal lobe damage. METHODS: The stop-signal reaction time (SSRT) test and a spatial working memory (SWM) task were administered to 20 adult patients with ADHD and a group of matched controls. The same tasks were administered to 21 patients with lesions to right frontal cortex and 19 patients with left frontal lesions. RESULTS: The SSRT test, but not choice reaction time, was significantly associated with search errors on the SWM task in both the adult ADHD and right frontal patients. In the right frontal patients, impaired performance on both variables was correlated with the volume of damage to the inferior frontal gyrus. CONCLUSIONS: Response inhibition and working memory impairments in ADHD may stem from a common pathologic process rather than being distinct deficits. Such pathology could relate to right frontal-cortex abnormalities in ADHD, consistent with prior reports, as well as with the demonstration here of a significant association between SSRT and SWM in right frontal patients.     

Neuropsychological function in adults with attention-deficit/hyperactivity disorder.

This article reviews the current state of the literature pertaining to the neuropsychological dysfunctions that are found in children and adults with attention-deficit/hyperactivity disorder (ADHD). Be-cause considerable controversy has existed about the nature and validity of adult ADHD, this article will aid clinicians in develop-ing a better understanding of the empirical literature on neuropsychological function in ADHD throughout the lifespan.     

Neurobehavioral and hemodynamic evaluation of Stroop and reverse Stroop interference in children with attention-deficit/hyperactivity disorder

Failure of executive function (EF) is a core symptom of attention-deficit/hyperactivity disorder (ADHD). However, various results have been reported and sufficient evidence is lacking. In the present study, we evaluated the characteristics of children with ADHD using the Stroop task (ST) and reverse Stroop task (RST) that reflects the inhibition function of EF. We compared children with ADHD, typically developing children (TDC), and children with autism spectrum disorder (ASD), which is more difficult to discriminate from ADHD. A total of 10 children diagnosed with ADHD, 15 TDC, and 11 children diagnosed with ASD, all matched by age, sex, language ability, and intelligence quotient, participated in this study. While each subject performed computer-based ST and RST with a touch panel, changes in oxygenated hemoglobin (oxy-Hb) were measured in the prefrontal cortex (PFC) by near-infrared spectroscopy (NIRS) to correlate test performance with neural activity. Behavioral performance significantly differed among 3 groups during RST but not during ST. The ADHD group showed greater color interference than the TDC group. In addition, there was a negative correlation between right lateral PFC (LPFC) activity and the severity of attention deficit. Children with ADHD exhibit several problems associated with inhibition of color, and this symptom is affected by low activities of the right LPFC. In addition, it is suggested that low hemodynamic activities in this area are correlated with ADHD.     

Efficacy and tolerability of OROS methylphenidate in Korean children with attention-deficit/hyperactivity disorder

This study evaluated the efficacy and tolerability in the initiation treatment of Concerta (OROS methylphenidate HCl) in Korean children with Attention-Deficit/Hyperactivity Disorder (AD/HD). One hundred and nineteen children with AD/HD were entered into a multi-center, open-label, four-week trial. The dosage of Concerta was adjusted by the investigators based on symptoms and safety assessments performed on a weekly basis. The safety of the drug and its efficacy for attention, behavior, and cognitive function were assessed. The primary outcome measures for efficacy were the Parent and Teacher IOWA Conners Rating Scales, Peer Interaction Items, and the Clinical Global Impression Scale. Cognitive tests (Continuous Performance Test, Matched Familiar Figure Test, Verbal Fluency Test, and Trail Making Test) were included as the secondary outcome measures. In most participants, OROS methylphenidate was well tolerated. There were significant improvements in attention, behavior, and function as measured by parents, teachers, and investigators. The benefit of the initiation of OROS methylphenidate in children with AD/HD was shown on the cognitive tests as well. These data provide support for the benefit of the once-daily methylphenidate preparation, Concerta in the treatment of Korean children with AD/HD. Children were initiated safely in this short-term trial, and its effectiveness was evident in the behavioral, as well as neuropsychological measurements.     

Treatment of adults with attention-deficit/hyperactivity disorder

This review focuses on the treatment of attention deficit hyperactivity disorder (ADHD) in adults. It briefly addresses prevalence, diagnostic and differential diagnostic issues specific to adults. Stimulant medication, non-stimulant medication, and psychosocial treatments are thoroughly reviewed. For each class of medication possible mechanism of action, efficacy and side effects are summarized. Special attention is given to the pharmacological treatment for patients with adult ADHD and various comorbidities. In summary, stimulant medications are most effective and combined medication and psychosocial treatment is the most beneficial treatment option for most adult patients with ADHD.