The neuropsychopharmacology of attention-deficit/hyperactivity disorder.

More than three decades of research has attempted to elucidate the neuropsychopharmacology of attention-deficit/hyperactivity disorder (ADHD). Stimulants, a principle treatment for the disorder, act on the norepinephrine (NE) and dopamine (DA) systems; this has led to a long-standing hypothesis of catecholamine dysfunction in ADHD. Animal studies show a clear role for NE and DA in the modulation of executive functions, which are often disturbed in persons with ADHD. Nonstimulant agents that are effective in the treatment of ADHD tend to affect the NE system, whereas those affecting only DA, or those that affect neither catecholamine, are less potent in reducing ADHD symptoms. Studies of the effects of NE and DA peripheral metabolites by ADHD pharmacotherapies show acute increases in levels of these catecholamines; however, their long-term turnover may be reduced. Imaging studies suggest stimulants increases DA levels in the brain, whereas some animal models of ADHD are more consistent with excessive DA activation in the disorder. Ultimately, ADHD therapy may modify activity in the NE and DA systems to a more optimal level, thus improving responses to environmental stimuli and enhancing working memory and executive function.     

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.     

Imaging the effects of methylphenidate on brain dopamine: new model on its therapeutic actions for attention-deficit/hyperactivity disorder.

Methylphenidate hydrochloride (MP) is an effective treatment for attention-deficit/hyperactivity disorder (ADHD), a common neurobehavioral disorder of childhood onset characterized by inattention, hyperactivity, and distractibility. Methylphenidate hydrochloride blocks the dopamine transporters (DAT), the main mechanism for removing dopamine (DA) from the synapse, is believed to be involved in its therapeutic properties. However, the mechanism(s) by which increases in DA improve symptomatology in ADHD are not completely understood. Our studies of the dopaminergic effects of MP in the human brain using positron emission tomography (PET) have shown that MP blocks DAT, and that extracellular DA increases in proportion to the level of blockade and the rate of DA release (modulated by DA cell firing). These DA increases are greater when MP is given concomitantly with a salient stimulus than with a neutral stimulus, documenting the context dependency of MP effects. Additionally, MP-induced increases in DA are associated with an enhanced perception of the stimulus as salient. We postulate the MP's therapeutic effects are due in part to its ability to enhance the magnitude of DA increases induced by stimuli that by themselves generate weak responses, enhancing their saliency and the attention and interest they elicit. We postulate that these effects would improve school performance.     

Pharmacological characterization of the norepinephrine and dopamine reuptake inhibitor EB-1020: implications for treatment of attention-deficit hyperactivity disorder

We report on the pharmacological, behavioral, and neurochemical characterization of a novel dual norepinephrine (NE)/dopamine (DA) transporter inhibitor EB‐1020 (1R,5S)‐1‐(naphthalen‐2‐yl)‐3‐azabicyclo[3.1.0]hexane HCl). EB‐1020 preferentially inhibited monoamine reuptake in cloned cell lines transfected with human transporters with IC₅₀ values of 6 and 38, respectively, for NE and DA transporters. In microdialysis studies, EB‐1020 markedly increased NE, and DA concentrations levels in rat prefrontal cortex in vivo with peak increases of 375 and 300%, respectively with the greatest effects on NE, and also increased DA extracellular concentrations in the striatum to 400% of baseline concentrations. Behavioral studies demonstrated that EB‐1020 dose‐dependently decreased immobility in the mouse tail suspension test of depression to 13% of control levels, and did not stimulate locomotor activity in adult rats in the optimal dose range. EB‐1020 dose‐dependently inhibited locomotor hyperactivity in juvenile rats lesioned with the neurotoxin 6‐hydroxydopamine (100 μg intracisternally) as neonates; a well‐established animal model for attention‐deficit hyperactivity disorder (ADHD). These data suggest that EB‐1020 mediates its actions by stimulating NE and DA neurotransmission, which are typically impaired in ADHD. Synapse, 2012. © 2012 Wiley Periodicals, Inc.     

Structural brain imaging of attention-deficit/hyperactivity disorder.

Many investigators have hypothesized that attention-deficit/hyperactivity disorder (ADHD) involves structural and functional brain abnormalities in frontal-striatal circuitry. Although our review suggests that there is substantial support for this hypothesis, a growing literature demonstrates widespread abnormalities affecting other cortical regions and the cerebellum. Because there is only one report studying adults with ADHD, this summary is based on children. A key limitation of the literature is that most of the studies until recently have been underpowered, using samples of fewer than 20 subjects per group. Nevertheless, these studies are largely consistent with the most comprehensive and definitive study (Castellanos et al 2002). Moreover, studies differ in the degree to which they address the influence of medications, comorbidities, or gender, and most have not addressed potentially important sources of heterogeneity such as family history of ADHD, subtype, or perinatal complications. Despite these limitations, a relatively consistent picture has emerged. The most replicated alterations in ADHD in childhood include significantly smaller volumes in the dorsolateral prefrontal cortex, caudate, pallidum, corpus callosum, and cerebellum. These results suggest that the brain is altered in a more widespread manner than has been previously hypothesized. Developmental studies are needed to address the evolution of this brain disorder into adulthood.     

Reduced midbrain dopamine transporter binding in male adolescents with attention-deficit/hyperactivity disorder: association between striatal dopamine markers and motor hyperactivity.

BACKGROUND: The hypothesis that altered dopamine transmission underlies hyperactive-inattentive behavior in children with attention-deficit/hyperactivity disorder (ADHD) is based on genetic studies and the efficacy of psychostimulants. Most of previous positron emission tomography (PET) and single photon emission tomography (SPET) studies have shown altered binding of dopamine markers in the basal ganglia. Yet, the functional role of the neurochemical disturbances are poorly understood. The purpose of our study was to examine dopamine transporter (DAT) and dopamine D2 receptor (D2R) binding in adolescents with ADHD and to search for its relationship with cognitive functions as well as locomotor hyperactivity. METHODS: Twelve adolescents with ADHD and 10 young adults were examined with PET using the selective radioligands [11C]PE2I and [11C]raclopride, indexing DAT and D2R density. The simplified reference tissue model was used to calculate binding potential (BP) values. Attention and motor behavior were investigated with a continuous performance task (CPT) and motion measurements. RESULTS: The BP value for [11C]PE2I and [11C]raclopride in the striatum of children with ADHD did not differ from that of the young adult control subjects. In the midbrain, however, the BP values for DAT were significantly lower (16%; p = .03) in children with ADHD. Dopamine D2 receptor binding in the right caudate nucleus correlated significantly with increased motor activity (r = .70, p = .01). CONCLUSIONS: The lower BP values for DAT in the midbrain suggest that dopamine signaling in subjects with ADHD is altered. Altered dopamine signaling might have a causal relationship to motor hyperactivity and might be considered as a potential endophenotype of ADHD.     

The dopamine transporter: relevance to attention deficit hyperactivity disorder (ADHD)

The dopamine transporter is elevated in adults with attention deficit hyperactivity disorder (ADHD) compared with healthy controls [Lancet 354 (1999) 2132]. The findings have been confirmed by others in a different population using a different probe for the dopamine transporter. Notwithstanding the need to confirm these findings in a multi-center trial, several hypotheses are presented to account for these observations. A premise that elevated transporter levels result from medication is not supported by current data. Other possibilities, including hypertrophy of dopamine neuronal terminals in the striatum, dysfunctional regulation of dopamine or dopamine receptors, or anomalies in the dopamine transporter gene are presented as hypotheses. The feasibility of exploring these mechanisms in animal models or in human subjects is explored.     

SPECT and PET of the dopamine transporter in attention-deficit/hyperactivity disorder

Abnormalities of frontostriatal circuits, which are modulated by dopamine, have been found by brain imaging studies in patients with attention-deficit/hyperactivity disorder (ADHD). With special radiolabeled ligands selective imaging of the dopamine transporter (DAT), which has a key function in dopamine metabolism, can be performed by SPECT and PET. Most of the studies showed a higher DAT availability in untreated patients with ADHD compared with controls. The relationship between DAT availability and a polymorphism of DAT1 gene in patients with ADHD is not clear and the results are controversial. It has been shown that methylphenidate lowers DAT availability very effectively in normal people and in patients with ADHD. First results seem to indicate that nonresponders to methylphenidate among ADHD patients have a low primary DAT availability, whereas patients with a good response to the drug have high DAT. Nicotine seems to lower DAT availability such as stimulant medication; this may explain the high percentage of smokers among patients with ADHD. Zinc is a DAT inhibitor and seems to have a positive therapeutic effect on ADHD symptoms. This article reviews the function and structure of the DAT, the results of DAT imaging with SPECT and PET, the relations between DAT availability and the DAT1 gene polymorphism, the influence of stimulants on DAT and the significance of DAT for therapeutic response, nicotine, zinc and psychotic symptoms in patients with ADHD.     

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, double-blind study of continuation treatment for attention-deficit/hyperactivity disorder after 1 year.

BACKGROUND: The efficacy of atomoxetine in maintaining symptom response following 1 year of treatment was assessed in children and adolescents (n = 163) with DSM-IV defined attention-deficit/hyperactivity disorder (ADHD). METHODS: Subjects had previously responded to atomoxetine acutely and had completed 1 year of double-blind atomoxetine treatment. They were then randomly assigned in double-blind fashion to continued atomoxetine or placebo substitution for 6 months. RESULTS: Atomoxetine was superior to placebo in preventing relapse (Wilcoxon test, p = .008) and in maintaining symptom response (ADHD Rating Scale IV score, p < .001). Among subjects assigned to discontinuation, the magnitude of symptom return was generally to a level of severity less than that observed at study entry. CONCLUSIONS: Following 1 year of treatment with atomoxetine, continued treatment over the ensuing 6 months was associated with superior outcomes compared with placebo substitution. However, there was considerable variability between individuals in the magnitude of symptom return after drug discontinuation, suggesting that some subjects treated with atomoxetine for a year with good results may consolidate gains made during drug treatment and could benefit from a medication-free trial to assess the need for ongoing drug treatment.     

Haplotype study of three polymorphisms at the dopamine transporter locus confirm linkage to attention-deficit/hyperactivity disorder.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is often treated using methylphenidate, a psychostimulant that inhibits the dopamine transporter. This led E.H. Cook and colleagues to consider the dopamine transporter locus (DAT1) as a primary candidate gene for ADHD. That group reported a significant association between ADHD and the 480-base pair (bp) allele of the variable number of tandem repeats (VNTR) polymorphism located in the 3' untranslated region of the DAT1 gene. This association was later replicated in additional studies. METHODS: The DAT1 gene has additional common polymorphisms in intron 9 and exon 9. We investigated the possibility of linkage of DAT1 and ADHD using the VNTR polymorphism and two additional common polymorphisms in 102 nuclear families with an ADHD proband. Using the transmission disequilibrium test, we examined the transmission of the alleles of each of these polymorphisms, as well as the haplotypes of the polymorphisms. RESULTS: We did not observe significant evidence for the biased transmission of the alleles of either the VNTR or the additional two polymorphisms when examined individually, although there was a trend for the biased transmission of the 480-bp allele of the VNTR. When we examined the haplotypes of the three polymorphisms we found significant evidence for biased transmission of one of the haplotypes containing the 480-bp VNTR allele. We also genotyped six additional DNA sequence variants of the DAT1 gene. However, these variants were not sufficiently polymorphic in our sample to be informative. Two of the DNA variants that result in an amino acid change, Ala559Val and Glu602Gly, were not observed in our sample. CONCLUSIONS: Our results support previous findings of an association between the DAT1 gene and 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.     

Milnacipran: a comparative analysis of human monoamine uptake and transporter binding affinity.

BACKGROUND: Though selective serotonin reuptake inhibitors have revolutionized the field of psychiatry with demonstrated efficacy in affective and anxiety disorders with minimal side effects, norepinephrine-serotonin reuptake inhibitors may provide efficacy similar to tricyclic antidepressants without the adverse side effects associated with tricyclic antidepressants. METHODS: The affinity and selectivity of milnacipran, duloxetine, venlafaxine, citalopram, amitriptyline, and nortriptyline were determined for the human serotonin, norepinephrine, and dopamine transporters. RESULTS: Both milnacipran and duloxetine were potent inhibitors of serotonin and norepinephrine uptake. Unlike duloxetine and venlafaxine, milnacipran appears serotonin transporter selective in binding (ratio = 2.61) and norepinephrine transporter selective in uptake (ratio =.45). CONCLUSIONS: Milnacipran's binding and uptake inhibition profile more closely resembles that of the tricyclic antidepressants than that of duloxetine. Whether these differences observed in vitro manifest themselves in vivo is not clear.     

Effect of visual attention on postural control in children with attention-deficit/hyperactivity disorder

We compared the effect of oculomotor tasks on postural sway in two groups of ADHD children with and without methylphenidate (MPH) treatment against a group of control age-matched children. Fourteen MPH-untreated ADHD children, fourteen MPH-treated ADHD children and a group of control children participated to the study. Eye movements were recorded using a video-oculography system and postural sway measured with a force platform simultaneously. Children performed fixation, pursuits, pro- and anti-saccades. We analyzed the number of saccades during fixation, the number of catch-up saccades during pursuits, the latency of pro- and anti-saccades; the occurrence of errors in the anti-saccade task and the surface and mean velocity of the center of pressure (CoP). During the postural task, the quality of fixation was significantly worse in both groups of ADHD children with respect to control children; in contrast, the number of catch-up saccades during pursuits, the latency of pro-/anti-saccades and the rate of errors in the anti-saccade task did not differ in the three groups of children. The surface of the CoP in MPH-treated children was similar to that of control children, while MPH-untreated children showed larger postural sway. When performing any saccades, the surface of the CoP improved with respect to fixation or pursuits tasks. This study provides evidence of poor postural control in ADHD children, probably due to cerebellar deficiencies. Our study is also the first to show an improvement on postural sway in ADHD children performing saccadic eye movements.     

Dopamine transporter imaging in adult patients with attention-deficit/hyperactivity disorder

The aim of this study was to provide in vivo evidence for the hypothesis that dopaminergic neurotransmission is altered in adult patients with attention-deficit/hyperactivity disorder (ADHD). We used high-resolution brain-dedicated single-photon emission computed tomography and the dopamine transporter (DAT) marker [¹²³I]FP-CIT in 17 adult treatment-naïve ADHD patients and 14 age-matched controls. Magnetic resonance imaging-based region of interest analysis was performed to quantify the DAT availability (expressed as a ratio of specific to non-displaceable binding, V₃″) in the striatum. Additionally, the specific radiotracer binding was assessed in the thalamus and the midbrain/brainstem regions (reflecting also the availability of the serotonin transporter to which [¹²³I]FP-CIT binds with moderate affinity). In the striatal areas of the ADHD patients, a significantly reduced specific tracer binding was found (V₃″: 5.18 ± 0.98; controls 6.36 ± 1.34). In contrast, the specific [¹²³I]FP-CIT binding did not differ from controls in the thalamus and midbrain/brainstem areas. These data indicate a reduced dopaminergic but not serotonergic transmitter reuptake function in adult ADHD. Further studies will have to deal with the question of whether these findings have the potential to influence treatment decisions in this complex disorder.