One-year prospective follow-up of pharmacological treatment in children with attention-deficit/hyperactivity disorder

Objectives  

To delineate the safety and tolerability profile of methylphenidate and atomoxetine in children and adolescents with attention deficit hyperactivity disorder (ADHD) monitored for more than 1 year.     

On the improvement of inhibitory response control and visuospatial attention by indirect and direct adrenoceptor agonists

Rationale  

The clinical efficacy of the monoamine and noradrenaline transporter inhibitors methylphenidate and atomoxetine in attention deficit/hyperactivity disorder implicates noradrenergic neurotransmission in modulating inhibitory response control processes. Nonetheless, it is unclear which adrenoceptor subtypes are involved in these effects.     

Modulation of high impulsivity and attentional performance in rats by selective direct and indirect dopaminergic and noradrenergic receptor agonists

Rationale

Impulsivity is associated with a number of psychiatric disorders, most notably attention deficit/hyperactivity disorder (ADHD). Drugs that augment catecholamine function (e.g. methylphenidate and the selective noradrenaline reuptake inhibitor atomoxetine) have clinical efficacy in ADHD, but their precise mechanism of action is unclear.

Objective

The objective of this study is to investigate the relative contribution of dopamine (DA) and noradrenaline (NA) to the therapeutic effects of clinically effective drugs in ADHD using rats selected for high impulsivity on the five-choice serial reaction time task (5CSRTT).

Methods

We examined the effects of direct and indirect DA and NA receptor agonists and selective DA and NA reuptake inhibitors in rats showing high and low levels of impulsivity on the 5CSRTT (designated high impulsive ??HI?? and low impulsive ??LI??, respectively). Drugs were administered by systemic injection in a randomized, counterbalanced manner.

Results

Low doses of quinpirole (a D2/D3 agonist) and sumanirole (a D2 agonist) selectively reduced impulsivity on the 5CSRTT, whilst higher doses resulted in increased omissions and slower response latencies. The NA reuptake inhibitor, atomoxetine, and the alpha-2 adrenoreceptor agonist, guanfacine, dose dependently decreased premature responding. The dopaminergic reuptake inhibitor GBR-12909 increased impulsivity, whereas the nonselective DA and NA reuptake inhibitor methylphenidate had no significant effect on impulsive responses in HI and LI rats.

Conclusions

These findings indicate that high impulsivity can be ameliorated in rats by drugs that mimic the effects of DA and NA, just as in ADHD, and that activation of D2/3 receptors selectively decreases high impulsivity on the 5CSRTT.     

Methylphenidate and atomoxetine normalise fronto-parietal underactivation during sustained attention in ADHD adolescents

Problems with sustained attention are a key clinical feature of Attention Deficit/Hyperactivity Disorder (ADHD) which also manifests in poor performance and abnormal fronto-striato-parietal activation during sustained attention. Methylphenidate and atomoxetine improve attention functions and upregulate abnormal fronto-cortical activation during executive function tasks in ADHD patients. Despite this, no functional Magnetic Resonance Imaging (fMRI) study has compared the effects of methylphenidate and atomoxetine on the neurofunctional substrates of sustained attention in ADHD. This randomised, double-blind, placebo-controlled, cross-over study investigated the comparative normalisation effects of methylphenidate and atomoxetine on fMRI correlates and performance in 14 ADHD adolescents relative to 27 age-matched healthy controls during a parametric sustained attention/vigilance task with progressively increasing load of sustained attention. ADHD patients were scanned three times under a single clinical dose of either methylphenidate, atomoxetine, or placebo in pseudo-randomised order. Healthy controls were scanned once and compared to patients under each drug condition to test for potential drug-normalisation effects. Relative to controls, ADHD boys under placebo were impaired in performance and had underactivation in predominantly right-hemispheric fronto-parietal, and striato-thalamic regions. Both drugs normalised all underactivations, while only methylphenidate improved performance deficits. Within patients, methylphenidate had a drug-specific effect of upregulating left ventrolateral prefrontal/superior temporal activation relative to placebo and atomoxetine, while both drugs increased activation of right middle/superior temporal cortex, posterior cingulate, and precuneus relative to placebo. The study shows shared normalisation effects of methylphenidate and atomoxetine on fronto-striato-thalamo-parietal dysfunction in ADHD during sustained attention but a drug-specific upregulation effects of methylphenidate on ventral fronto-temporal regions.     

Monoaminergic modulation of behavioural and electrophysiological indices of error processing

Rationale

Error processing is a critical executive function that is impaired in a large number of clinical populations. Although the neural underpinnings of this function have been investigated for decades and critical error-related components in the human electroencephalogram (EEG), such as the error-related negativity (ERN) and the error positivity (Pe), have been characterised, our understanding of the relative contributions of key neurotransmitters to the generation of these components remains limited.

Objectives

The current study sought to determine the effects of pharmacological manipulation of the dopamine, noradrenaline and serotonin neurotransmitter systems on key behavioural and event-related potential correlates of error processing.

Methods

A randomised, double-blinded, placebo-controlled, crossover design was employed. Monoamine levels were manipulated using the clinically relevant drugs methylphenidate, atomoxetine and citalopram, in comparison to placebo. Under each of the four drug conditions, participants underwent EEG recording while performing a flanker task.

Results

Only methylphenidate produced significant improvement in performance accuracy, which was without concomitant slowing of reaction time. Methylphenidate also increased the amplitude of an early electrophysiological index of error processing, the ERN. Citalopram increased the amplitude of the correct-response negativity, another component associated with response processing.

Conclusions

The effects of methylphenidate in this study are consistent with theoretical accounts positing catecholamine modulation of error monitoring. Our data suggest that enhancing catecholamine function has the potential to remediate the error-monitoring deficits that are seen in a wide range of psychiatric conditions.     

Inhibition of G-Protein-Activated Inwardly Rectifying K+ Channels by the Selective Norepinephrine Reuptake Inhibitors Atomoxetine and Reboxetine

Atomoxetine and reboxetine are commonly used as selective norepinephrine reuptake inhibitors (NRIs) for the treatment of attention-deficit/hyperactivity disorder and depression, respectively. Furthermore, recent studies have suggested that NRIs may be useful for the treatment of several other psychiatric disorders. However, the molecular mechanisms underlying the various effects of NRIs have not yet been sufficiently clarified. G-protein-activated inwardly rectifying K⁺ (GIRK or Kir3) channels have an important function in regulating neuronal excitability and heart rate, and GIRK channel modulation has been suggested to be a potential treatment for several neuropsychiatric disorders and cardiac arrhythmias. In this study, we investigated the effects of atomoxetine and reboxetine on GIRK channels using the Xenopus oocyte expression assay. In oocytes injected with mRNA for GIRK1/GIRK2, GIRK2, or GIRK1/GIRK4 subunits, extracellular application of atomoxetine or reboxetine reversibly reduced GIRK currents. The inhibitory effects were concentration-dependent, but voltage-independent, and time-independent during each voltage pulse. However, Kir1.1 and Kir2.1 channels were insensitive to atomoxetine and reboxetine. Atomoxetine and reboxetine also inhibited GIRK currents induced by activation of cloned A₁ adenosine receptors or by intracellularly applied GTPγS, a nonhydrolyzable GTP analogue. Furthermore, the GIRK currents induced by ethanol were concentration-dependently inhibited by extracellularly applied atomoxetine but not by intracellularly applied atomoxetine. The present results suggest that atomoxetine and reboxetine inhibit brain- and cardiac-type GIRK channels, revealing a novel characteristic of clinically used NRIs. GIRK channel inhibition may contribute to some of the therapeutic effects of NRIs and adverse side effects related to nervous system and heart function.     

Inhibition of the norepinephrine transporter improves behavioral flexibility in rats and monkeys

Rationale

Poor cognitive control, including reversal learning deficits, has been reported in children with attention deficit hyperactivity disorder, in stimulant-dependent humans, and in animal models of these disorders; these conditions have each been associated with abnormal catecholaminergic function within the prefrontal cortex.

Objectives

In the current studies, we sought to explore how elevations in extracellular catecholamine levels, produced by pharmacological inhibition of catecholamine reuptake proteins, affect behavioral flexibility in rats and monkeys.

Materials and methods

Adult male Long–Evans rats and vervet monkeys were trained, respectively, on a four-position discrimination task or a three-choice visual discrimination task. Following systemic administration of pharmacological inhibitors of the dopamine and/or norepinephrine membrane transporters, rats and monkeys were exposed to retention or reversal of acquired discriminations.

Results

In accordance with our a priori hypothesis, we found that drugs that inhibit norepinephrine transporters, such as methylphenidate, atomoxetine, and desipramine, improved reversal performance in rats and monkeys; this was mainly due to a decrease in the number of perseverative errors. Interestingly, the mixed dopamine and norepinephrine transporters inhibitor methylphenidate, if anything, impaired performance during retention in both rats and monkeys, while administration of the selective dopamine transporter inhibitor GBR-12909 increased premature responses but did not alter reversal learning performance.

Conclusions

Our results suggest that pharmacological inhibition of the membrane norepinephrine, but not membrane dopamine, transporter is associated with enhanced behavioral flexibility. These data, combined with earlier reports, may indicate that enhanced extracellular catecholamine levels in cortical regions, secondary to norepinephrine reuptake inhibition, improves multiple aspects of inhibitory control over responding in rats and monkeys.     

A review of the abuse potential assessment of atomoxetine: a nonstimulant medication for attention-deficit/hyperactivity disorder

Rationale

Treatment of attention-deficit/hyperactivity disorder (ADHD) has for many years relied on psychostimulants, particularly various formulations of amphetamines and methylphenidate. These are central nervous system stimulants and are scheduled because of their abuse potential. Atomoxetine (atomoxetine hydrochloride; Strattera®) was approved in 2002 for treatment of ADHD, and was the first nonstimulant medication approved for this disorder. It was classified as an unscheduled medication indicating a low potential for abuse. However, the abuse potential of atomoxetine has not been reviewed.

Objectives

In this article, we review the evidence regarding abuse potential of atomoxetine, a selective inhibitor of the presynaptic norepinephrine transporter, which is unscheduled/unrestricted in all countries where it is approved.

Methods

Results from receptor binding, in vitro electrophysiology, in vivo microdialysis, preclinical behavioral, and human laboratory studies have been reviewed.

Results

Atomoxetine has no appreciable affinity for, or action at, central receptors through which drugs of abuse typically act, i.e., dopamine transporters, GABA_A receptors, and opioid μ receptors. In behavioral experiments in rodents, atomoxetine does not increase locomotor activity, and in drug discrimination studies, its profile is similar to that of drugs without abuse potential. Atomoxetine does not serve as a reinforcer in monkey self-administration studies, and human laboratory studies suggest that atomoxetine does not induce subjective effects indicative of abuse.

Conclusion

Neurochemical, preclinical, and early clinical studies predicted and supported a lack of abuse potential of atomoxetine, which is consistent with the clinical trial and postmarketing spontaneous event data in the past 10 years.     

Atomoxetine Treatment Strengthens an Anti-Correlated Relationship between Functional Brain Networks in Medication-Na?ve Adults with Attention-Deficit Hyperactivity Disorder: A Randomized Double-Blind Placebo-Controlled Clinical Trial

Background:

Although atomoxetine demonstrates efficacy in individuals with attention-deficit hyperactivity disorder, its treatment effects on brain resting-state functional connectivity remain unknown. Therefore, we aimed to investigate major brain functional networks in medication-naïve adults with attention-deficit hyperactivity disorder and the efficacy of atomoxetine treatment on resting-state functional connectivity.

Methods:

After collecting baseline resting-state functional MRI scans from 24 adults with attention-deficit hyperactivity disorder (aged 18–52 years) and 24 healthy controls (matched in demographic characteristics), the participants with attention-deficit hyperactivity disorder were randomly assigned to atomoxetine (n=12) and placebo (n=12) arms in an 8-week, double-blind, placebo-controlled trial. The primary outcome was functional connectivity assessed by a resting-state functional MRI. Seed-based functional connectivity was calculated and compared for the affective, attention, default, and cognitive control networks.

Results:

At baseline, we found atypical cross talk between the default, cognitive control, and dorsal attention networks and hypoconnectivity within the dorsal attention and default networks in adults with attention-deficit hyperactivity disorder. Our first-ever placebo-controlled clinical trial incorporating resting-state functional MRI showed that treatment with atomoxetine strengthened an anticorrelated relationship between the default and task-positive networks and modulated all major brain networks. The strengthened anticorrelations were associated with improving clinical symptoms in the atomoxetine-treated adults.

Conclusions:

Our results support the idea that atypical default mode network task-positive network interaction plays an important role in the pathophysiology of adult attention-deficit hyperactivity disorder. Strengthening this atypical relationship following atomoxetine treatment suggests an important pathway to treat attention-deficit hyperactivity disorder.     

Assessing attention orienting in mice: a novel touchscreen adaptation of the Posner-style cueing task

Atypical attention orienting has been found to be impaired in many neuropsychological disorders, but the underlying neural mechanism remains unclear. Attention can be oriented exogenously (i.e., driven by salient stimuli) or endogenously (i.e., driven by one’s goals or intentions). Genetic mouse models are useful tools to investigate the neurobiology of cognition, but a well-established assessment of attention orienting in mice is missing. This study aimed to adapt the Posner task, a widely used attention orienting task in humans, for use in mice using touchscreen technology and to test the effects of two attention-modulating drugs, methylphenidate (MPH) and atomoxetine (ATX), on the performance of mice during this task. In accordance with human performance, mice responded more quickly and more accurately to validly cued targets compared to invalidly cued targets, thus supporting mice as a valid animal model to study the neural mechanisms of attention orienting. This is the first evidence that mice can be trained to voluntarily maintain their nose-poke on a touchscreen and to complete attention orienting tasks using exogenous peripheral cues and endogenous symbolic cues. The results also showed no significant effects of MPH and ATX on attention orienting, although MPH improved overall response times in mice during the exogenous orienting task. In summary, the current study provides a critical translational task for assessing attention orienting in mice and to investigate the effects of attention-modulating drugs on attention orienting.Subject terms: Pharmacology, Attention     

Similar effects of the selective noradrenaline reuptake inhibitor atomoxetine on three distinct forms of impulsivity in the rat.

Atomoxetine is a noradrenaline-specific reuptake inhibitor used clinically for the treatment of childhood and adult attention deficit hyperactivity disorder (ADHD). Studies in human volunteers and patient groups have shown that atomoxetine improves stop-signal reaction time (SSRT) performance, an effect consistent with a reduction in motor impulsivity. However, ADHD is a heterogeneous disorder and it is of interest to determine whether atomoxetine is similarly effective against other forms of impulsivity, as well as the attentional impairment present in certain subtypes of ADHD. The present study examined the effects of atomoxetine on impulsivity using an analogous SSRT task in rats and two additional tests of impulsivity; delay discounting of reward and the five-choice serial reaction time task (5CSRTT), the latter providing an added assessment of sustained visual attention. Atomoxetine produced a significant dose-dependent speeding of SSRT. In addition, atomoxetine produced a selective, dose-dependent decrease in premature responding on the 5CSRTT. Finally, on the delay-discounting task, atomoxetine significantly decreased impulsivity by increasing preference for the large-value reward across increasing delay. These findings conclusively demonstrate that atomoxetine decreases several distinct forms of impulsivity in rats. The apparent contrast of these effects with stimulant drugs such as amphetamine and methylphenidate, which generally act to increase impulsivity on the 5CSRTT, may provide new insights into the mechanisms of action of stimulant and nonstimulant drugs in ADHD.     

Methylphenidate produces selective enhancement of declarative memory consolidation in healthy volunteers

Rationale

Methylphenidate inhibits the reuptake of dopamine and noradrenaline and is used to treat children with attention deficit hyperactivity disorder (ADHD). Besides reducing behavioral symptoms, it improves their cognitive function. There are also observations of methylphenidate-induced cognition enhancement in healthy adults, although studies in this area are relatively sparse. We assessed the possible memory-enhancing properties of methylphenidate.

Objective

In the current study, the possible enhancing effects of three doses of methylphenidate on declarative and working memory, attention, response inhibition and planning were investigated in healthy volunteers.

Methods

In a double blind placebo-controlled crossover study, 19 healthy young male volunteers were tested after a single dose of placebo or 10, 20 or 40?mg of methylphenidate. Cognitive performance testing included a word learning test as a measure of declarative memory, a spatial working memory test, a set-shifting test, a stop signal test and a computerized version of the Tower of London planning test.

Results

Declarative memory consolidation was significantly improved relative to placebo after 20 and 40?mg of methylphenidate. Methylphenidate also improved set shifting and stopped signal task performance but did not affect spatial working memory or planning.

Conclusions

To the best of our knowledge, this is the first study reporting enhanced declarative memory consolidation after methylphenidate in a dose-related fashion over a dose range that is presumed to reflect a wide range of dopamine reuptake inhibition.     

Treatment stabilization in children and adolescents with attention-deficit/hyperactivity disorder: data from the Netherlands

Abstract

Objective:

To evaluate the number of patients reaching stable treatment with a stimulant (methylphenidate or dexamphetamine) or non-stimulant (atomoxetine) attention-deficit/hyperactivity disorder (ADHD) medication approved for use in the Netherlands, and the time to treatment stabilization among children and adolescents aged 6–17 years.     

Discriminative-stimulus, self-reported, performance, and cardiovascular effects of atomoxetine in methylphenidate-trained humans

Atomoxetine is marketed as a nonstimulant medication indicated for the treatment of attention-deficit/hyperactivity disorder in adults. Previous laboratory research suggests that atomoxetine has limited abuse potential but that some of its behavioral effects might overlap with traditional psychomotor stimulants like methylphenidate and d-amphetamine. A drug with this profile might be useful for the treatment of stimulant dependence. The aim of this experiment was to compare the discriminative-stimulus and self-reported effects of atomoxetine with methylphenidate, damphetamine, and triazolam in humans who had acquired a methylphenidate (30 mg) discrimination. Six healthy subjects with a recent history of nontherapeutic stimulant use were enrolled in this outpatient study. After subjects acquired the methylphenidate discrimination, a range of doses of methylphenidate (5-30 mg), atomoxetine (15-90 mg), d-amphetamine (2.5-15 mg), triazolam (0.06-0.375 mg), and placebo were tested. To more fully characterize the behavioral effects of atomoxetine, a battery of self-reported drug-effect questionnaires, a performance task, and cardiovascular assessments were also included. Methylphenidate and d-amphetamine increased drug-appropriate responding and produced typical stimulant-like effects (e.g., increased ratings of "Active, Alert, Energetic"). Atomoxetine partially substituted for methylphenidate (i.e., 33%-50%) and produced some dose-dependent, stimulant-like, subject-rated drug effects, although the magnitude of these effects was less than d-amphetamine and methylphenidate and generally did not attain statistical significance. These data suggest that the behavioral effects of atomoxetine overlap to a small degree with psychomotor stimulants and that it has low abuse potential.     

托莫西汀与哌甲酯治疗注意缺陷多动障碍患儿的疗效和安全性比较

目的:比较托莫西汀与哌甲酯治疗注意缺陷多动障碍患儿的疗效和安全性。方法:选择我院收治的注意缺陷多动障碍患儿共52例,随机分为托莫西汀组与哌甲酯组各26例,治疗结束后观察两组患儿的治疗有效率、ADHDRS-IV-Parent:Inv评分以及CPRS-R:S评分。结果:托莫西汀组与哌甲酯组的治疗有效率相近。治疗后托莫西汀组与哌甲酯组的ADHDRS-IV-Parent:Inv各项评分均明显下降,与治疗前比较差异均有统计学意义(P<0.05)。治疗后托莫西汀组与哌甲酯组CPRS-R:S评分的分数均明显下降,与治疗前比较差异均有统计学意义(P<0.05)。托莫西汀组的多动分变化值大于哌甲酯组,差异有统计学意义(P<0.05),两组患儿在治疗过程中均未发现严重的药物不良反应。结论:托莫西汀的疗效与哌甲酯相近,都具有良好的安全性,值得临床推广。     

Methylphenidate significantly improves declarative memory functioning of adults with ADHD

Background  

Declarative memory deficits are common in untreated adults with attention-deficit hyperactivity disorder (ADHD), but limited evidence exists to support improvement after treatment with methylphenidate. The objective of this study was to examine the effects of methylphenidate on memory functioning of adults with ADHD.     

Abuse liability assessment of atomoxetine in a drug-abusing population

BACKGROUND: Atomoxetine is a non-amphetamine medication approved to treat ADHD in children, adolescents, and adults. Previous studies demonstrated low abuse potential for atomoxetine in recreational drug users. This study assessed the abuse potential of atomoxetine in stimulant-preferring drug abusers compared to methylphenidate and phentermine as positive controls and desipramine and placebo as negative controls. METHODS: Forty male and female, 32-53 years old stimulant-preferring drug abusers completed this balanced Latin-square designed study. Subjects received acute, double-blind doses of placebo, desipramine (100 and 200 mg), methylphenidate (90 mg), phentermine (60 mg), and atomoxetine (45, 90, and 180 mg). Subjective and physiological effects were collected for 24 h following each drug treatment. RESULTS: Methylphenidate and phentermine were liked significantly more than placebo, atomoxetine, or desipramine. No atomoxetine dose was liked significantly more than placebo and liking scores for atomoxetine were similar to, or significantly lower than, desipramine, as assessed by the Drug Rating Questionnaire-Subject. While atomoxetine 45 and 180 mg did not significantly change any Addiction Research Center Inventory (ARCI) scores, atomoxetine 90 mg significantly increased A and BG stimulant scores of the ARCI and both methylphenidate and phentermine produced greater A and BG increases than any atomoxetine dose and also increased MBG (euphoria) scores relative to placebo. CONCLUSIONS: Atomoxetine has significantly less abuse liability than methylphenidate or phentermine and no greater abuse liability than desipramine.     

Early methylphenidate exposure enhances cocaine self-administration but not cocaine-induced conditioned place preference in young adult rats

Rationale  

Previous studies in rodents show that early exposure to methylphenidate alters later responsiveness to drugs of abuse. An interesting feature of these studies is that early methylphenidate treatment decreases the rewarding value of cocaine when measured by conditioned place preference (CPP), but the same treatment increases cocaine self-administration.     

Evaluation of the reinforcing effects of atomoxetine in monkeys: comparison to methylphenidate and desipramine

Atomoxetine is a selective norepinephrine (NE) reuptake blocker that has recently been marketed for the treatment of attention deficit hyperactivity disorder. The purpose of the present study was to evaluate the self-administration of atomoxetine in an animal model predictive of abuse liability in humans. Rhesus monkeys (N = 5) were prepared with chronic intravenous catheters and allowed to self-administer cocaine or saline during alternating baseline sessions. When behavior was stable, atomoxetine (0.03-3.0 mg/kg per injection), desipramine (0.1-3.0 mg/kg per injection), methylphenidate (0.001-0.1 mg/kg per injection), or their vehicles were substituted for baseline conditions. Methylphenidate consistently maintained responding above the levels maintained by its vehicle. Atomoxetine and desipramine failed to reliably maintain self-administration above vehicle levels in four of five individual monkeys. These results predict that atomoxetine, in contrast to methylphenidate but like desipramine, will lack reinforcing effects and abuse potential in humans.