Atomoxetine For Attention Deficit Hyperactivity Disorder Research Articles

Comparative efficacy and safety of methylphenidate and atomoxetine for attention-deficit hyperactivity disorder in children and adolescents: Meta-analysis based on head-to-head trials

ABSTRACTIntroduction: Comparative efficacy and safety are important issues for appropriate drug selection for attention-deficit hyperactivity disorder (ADHD) treatment. Therefore we conducted a meta-analysis, where we compared atomoxetine (ATX) and methylphenidate (MPH) for ADHD treatment in children and adolescents. Method: Literature retrieval was conducted in relevant databases from their inception to April 2016 to select head-to-head trials that compared ATX and MPH in children and adolescents. Outcomes like response rate, ADHD Rating Scale (ADHD–RS) score, and adverse events were compared between ATX and MPH treatments. The standardized mean difference (SMD) and risk ratio (RR) with their corresponding 95% confidence intervals (CIs) were used as the effect size for continuous data or dichotomous data, respectively. Results: Eleven eligible randomized-controlled trials were included, and two of them were double-blind, while the remaining were open-label. Compared to ATX, MPH showed a higher response rate (RR = 1.14, 95% CI [1. 09, 1.20]), decreased inattention (SMD = −0.13, 95% CI [−0.25, −0.01]) and lower risk of adverse events (drowsiness: RR = 0.17, 95% CI [0.11, 0.26; nausea: RR = 0.49; 95% CI [0.29, 0.85; vomiting: RR = 0.41, 95% CI [0.27, 0.63]). However, MPH presented a higher risk of insomnia than ATX (RR = 2.27, 95% CI [1.63, 3.15], p < .01). Conclusion: Results of the meta-analysis add additional evidence of the effectiveness of both ATX and MPH and suggest that MPH should be a first treatment option in most patients with ADHD.

Factors affecting treatment adherence to atomoxetine in ADHD: a systematic review.

The purpose of this paper was to systematically review the literature related to research about the factors affecting treatment adherence and discontinuation of atomoxetine in pediatric, adolescent, and adult patients with attention-deficit/hyperactivity disorder (ADHD). Medline was systematically searched using the following prespecified terms: “ADHD”, “Adherence”, “Compliance”, “Discontinuation”, and “Atomoxetine”. We identified 31 articles that met all inclusion and exclusion criteria. The findings from this review indicate that persistence and adherence to atomoxetine treatment were generally high. Factors found to influence adherence and nonadherence to atomoxetine treatment in ADHD in this review include age, sex, the definition of response used, length of treatment, initial dose of treatment, comorbid conditions, and reimbursement. Tolerability was cited as an important reason for treatment discontinuation. More research is needed to understand those factors that can help to identify patients at risk for poor adherence and interventions that could improve treatment adherence early in the stage of this illness to secure a better long-term prognosis.

Priapism associated with the use of stimulant medications and atomoxetine for attention-deficit/hyperactivity disorder in children.

To review the association of priapism with stimulant medications and atomoxetine commonly used in the treatment of attention-deficit/hyperactivity disorder (ADHD). A comprehensive literature search was conducted through PubMed (1966-May 15, 2014) using the search terms priapism, methylphenidate, amphetamine, atomoxetine, attention-deficit disorder with hyperactivity, and pediatrics. Google Scholar, Scopus, and the Food and Drug Administration (FDA) Web site were also searched. References from identified literature were also reviewed. All identified literature focused on ADHD treatment. Literature regarding priapism caused by methylphenidate, amphetamines, and atomoxetine were included. Stimulant medications and atomoxetine have been linked to the occurrence of priapism in children. Specifically, methylphenidate has been implicated in a recent FDA safety announcement warning as a result of 15 case reports (mean age = 12.5 years), and thus, the drug label and medication guides have been updated to reflect this concern. Prolonged erections and priapism occurred with immediate- and long-acting products, dose increases, and drug withdrawal periods. Priapism has also occurred in 4 patients taking amphetamines and one 11-year-old patient taking atomoxetine for ADHD. Priapism has been associated with stimulants, amphetamines, and atomoxetine use for ADHD in children. Providers and health care practitioners should educate male patients prescribed these ADHD medications as well as caregivers regarding the signs, symptoms, and complications with priapism. Discontinuation and evaluation of the medication is warranted if this adverse drug reaction occurs. Depending on the priapism subtype, other products may be initiated or medications not associated with priapism may be utilized.

A randomized controlled trial investigation of a non-stimulant in attention deficit hyperactivity disorder (ACTION): rationale and design.

BackgroundThe ACTION study (Attention deficit hyperactivity disorder Controlled Trial Investigation Of a Non-stimulant) is a multi-center, double-blind, randomized cross-over trial of the non-stimulant medication, Atomoxetine, in children and adolescents with attention deficit hyperactivity disorder (ADHD). The primary aims are to examine the efficacy of atomoxetine for improving cognition and emotional function in ADHD and whether any improvements in these outcomes are more pronounced in participants with comorbid anxiety; and to determine if changes in these outcomes after atomoxetine are more reliable than changes in diagnostic symptoms of ADHD. This manuscript will describe the methodology and rationale for the ACTION study.MethodsChildren and adolescents aged 6 - 17 y with ADHD will be enrolled. Clinical interview and validated scales will be used to confirm diagnosis and screen for exclusion criteria, which include concurrent stimulant use, and comorbid psychiatric or neurological conditions other than anxiety. Three assessment sessions will be conducted over the 13-week study period: Session 1 (Baseline, pre-treatment), Session 2 (six weeks, atomoxetine or placebo), and Session 3 (13 weeks, cross-over after one-week washout period). The standardized touch-screen battery, "IntegNeuro™", will be used to assess cognitive and emotional function. The primary measure of response will be symptom ratings, while quality of life will be a secondary outcome. Logistic regression will be used to determine predictors of treatment response, while repeated measures of analysis will determine any differences in effect of atomoxetine and placebo.ResultsThe methodology for the ACTION study has been detailed.ConclusionsThe ACTION study is the first controlled trial to investigate the efficacy of atomoxetine using objective cognitive and emotional function markers, and whether these objective measures predict outcomes with atomoxetine in ADHD with and without comorbid anxiety. First enrollment was in March 2008. The outcomes of this study will be a significant step towards a 'personalized medicine' (and therefore a more efficient) approach to ADHD treatment.Trial registrationAustralian and New Zealand Clinical Trials Registry ANZCTRN12607000535471.

Atomoxetine for ADHD: Response to Treatment & Cytochrome Activity

Source: ter Laak MA, Temmink AH, Koeken A, et al. Recognition of impaired atomoxetine metabolism because of low CYP2D6 activity. Pediatr Neurol. 2010; 43(3): 159– 162; doi: 10.1016/j.pediatrneurol.2010.04.004Investigators from the Netherlands performed a study to determine whether the genotypic pattern of cytochrome P450 pathway activity has a characteristic pattern associated with delayed response and adverse effects from atomoxetine in a series of children with attention deficit hyperactivity disorder (ADHD). Atomoxetine is a nonstimulant medication used to treat ADHD which is metabolized mainly through the cytochrome P450 2D6 (CYP2D6) enzyme pathway. Polymorphisms of this pathway are common in Caucasians and can result in a reduced ability to metabolize atomoxetine, leading to variability in efficacy and tolerability.Of 100 patients being treated with atomoxetine for ADHD, 10 took longer than 9 weeks to achieve therapeutic effects and experienced adverse effects attributable to the drug. These 10 patients underwent genotyping. Eight of the 10 patients showed compromised CYP2D6 activity, and 2 had normal activity. Four of eight patients with compromised CYP2D6 activity stopped atomoxetine treatment because of initial adverse effects (gastrointestinal, sleeping, malaise, and mood disorders). In four other patients atomoxetine doses were reduced after genotyping, leading to better tolerability and efficacy. A patient with normal CYP2D6 activity, but compromised CYP2C19 activity (a minor pathway in atomoxetine metabolism), responded better after a change in dose time to morning instead of evening. The cost versus benefit ratio of prospective cytochrome P450 2D6 genotyping before atomoxetine treatment requires investigation. The authors conclude that prescribing physicians should consider genotyping prior to treatment with atomoxetine because of differences in CYP2D6 activity which impact clinical responses.Dr Millichap has disclosed no financial relationship relevant to this commentary. This commentary does not contain a discussion of an unapproved/investigative use of a commercial product/device.Atomoxetine HCl is a selective norepinephrine reuptake inhibitor, approved in 2002 for the treatment of ADHD in adults and children aged 6 years and older. Atomoxetine is used as an alternative to stimulant medication in children with ADHD complicated by tics or Tourette syndrome. It is also sometimes preferred in children with ADHD complicated by a tendency to seizures or sleep disorder.1Both inattentive and hyperactive/impulsive symptoms appear to be significantly reduced by atomoxetine, compared with placebo. Adverse events are infrequent, and include decreased appetite, somnolence, and fatigue.2–4 Suicidal ideation/behavior occurs in fewer than 1.6% and potentially significant hepatic changes in 2% of children treated with atomoxetine.3The recommended daily dose of atomoxetine is 1.2 mg/kg, ranging from a 0.5 mg/kg initial dose to a maximum of 1.8 mg/kg. Capsules are available in strengths as low as 10 mg for young children and as high as 80 and 100 mg for adults.The current study suggests that testing for cytochrome P450 2D6 genotyping before starting atomoxetine treatment may help avoid both overdosing and underdosing the medication. The cost:benefit ratio of initial enzyme testing of cytochrome P450 2D6 versus close monitoring of response to carefully graded doses of atomoxetine requires further study. A personal enquiry regarding the cost to a patient of cytochrome P450 2D6 genotyping is quoted by one laboratory at approximately $700; the cost of testing for CYP450 C19, a variant of lesser importance, is slightly greater. Failed treatment with recommended dose schedules of atomoxetine or early occurrence of side effects should alert clinicians to the possibility of underlying abnormal cytochrome enzyme activity.Assessing an individual child’s potential to metabolize a drug prior to prescribing it reflects the burgeoning in primary care of individualized medicine based on our enhanced understanding of biochemical genetics and new technologies. The methodologic challenges of cost versus benefit of such testing are daunting; among the factors to weigh are the costs of the therapy being considered, the costs of testing, and the cost and severity of the adverse consequences of treatment.In early September the United States Food and Drug Administration (FDA) approved the marketing of generic atomoxetine hydrochloride capsules in strengths of 10, 18, 25, 40, 60, and 100 mg. The annual sales of both branded and generics is estimated to be over US$ 530 million in the United States market according to The Economic Times of India.5

Evaluation of [ 11C]MRB for assessment of occupancy of norepinephrine transporters: Studies with atomoxetine in non-human primates

[ 11C]MRB is one of the most promising radioligands used to measure brain norepinephrine transporters (NET) with positron emission tomography (PET). The objective of this study was to evaluate the suitability of [ 11C]MRB for drug occupancy studies of NET using atomoxetine (ATX), a NET uptake inhibitor used in the treatment of depression and attention-deficit hyperactivity disorder (ADHD). A second goal of the study was identification of a suitable reference region. Ten PET studies were performed in three anesthetized rhesus monkeys following an infusion of ATX or placebo. [ 11C]MRB arterial input functions and ATX plasma levels were also measured. A dose-dependent reduction of [ 11C]MRB volume of distribution was observed after correction for [ 11C]MRB plasma free fraction. ATX IC 50 was estimated to be 31 ± 10 ng/mL plasma. This corresponds to an effective dose ( ED 50) of 0.13 mg/kg, which is much lower than the therapeutic dose of ATX in ADHD (1.0–1.5 mg/kg). [ 11C]MRB binding potential BP ND in the thalamus was estimated to be 1.8 ± 0.3. Defining a reference region for a NET radiotracer is challenging due to the widespread and relatively uniform distribution of NET in the brain. Three regions were evaluated for use as reference region: caudate, putamen and occipital cortex. Caudate was found to be the most suitable for preclinical drug occupancy studies in rhesus monkeys. The IC 50 estimate obtained using MRTM2 BP ND without arterial blood sampling was 21 ± 3 ng/mL (using caudate as the reference region). This study demonstrated that [ 11C]MRB is suitable for drug occupancy studies of NET.

Spotlight on Atomoxetine in Attention-Deficit Hyperactivity Disorder in Children and Adolescents†

Atomoxetine (Strattera) is a selective noradrenaline (norepinephrine) reuptake inhibitor that is not classified as a stimulant, and is indicated for use in patients with attention-deficit hyperactivity disorder (ADHD). Atomoxetine is effective and generally well tolerated. It is significantly more effective than placebo and standard current therapy and does not differ significantly from, or is noninferior to, immediate-release methylphenidate; however, it is significantly less effective than the extended-release methylphenidate formulation OROS methylphenidate (hereafter referred to as osmotically released methylphenidate) and extended-release mixed amfetamine salts. Atomoxetine can be administered either as a single daily dose or split into two evenly divided doses, has a negligible risk of abuse or misuse and is not a controlled substance in the US. Atomoxetine is particularly useful for patients at risk of substance abuse, as well as those who have co-morbid anxiety or tics, or who do not wish to take a controlled substance. Thus, atomoxetine is a useful option in the treatment of ADHD in children and adolescents.

A Haplotype of the Norepinephrine Transporter (Net) Gene Slc6a2 is Associated with Clinical Response to Atomoxetine in Attention-Deficit Hyperactivity Disorder (ADHD)

Atomoxetine is a specific inhibitor of the norepinephrine transporter (NET) that has demonstrated efficacy in the treatment of children with attention-deficit hyperactivity disorder (ADHD). We investigated whether polymorphisms in the NET/SLC6A2 gene may influence atomoxetine response in ADHD. Two independent cohorts of 160 and 105 ADHD children treated for 6 weeks with atomoxetine (0.5-1.8 mg/kg per day) were genotyped on CYP2D6, which metabolizes atomoxetine, and 108 single nucleotide polymorphisms in the NET/SLC6A2 gene. Response was defined as a minimum decrease of 25% in ADHD Rating Scale IV-Parent Version and a Clinical Global Impression-Severity (CGI-S) score less than or equal to 2 at week 6. Interindividual response was independent of the genetic variants of CYP2D6. Significant (p<0.05) associations between 20 NET/SLC6A2 single nucleotide polymorphisms (SNPs) and clinical efficacy in atomoxetine responders, compared with non-responders, were observed. The genomic region across exons 4 to 9 of NET/SLC6A2, where 36 SNPs have been genotyped, was associated with treatment response in both cohorts (p<0.01, odds ratio=2.2 and p=0.026, odds ratio=6.3, respectively), in the combined cohort (p<0.01, odds ratio=1.83), and in the subgroup of Caucasians only (p=0.02, odds ratio=1.8). Clinical efficacy of atomoxetine treatment in ADHD shows potential dependence upon a series of genetic polymorphisms of its mechanistic target, the norepinephrine transporter. Taking into account the high heritability of ADHD, the significance of the present finding and replication of a similar haplotype allele sequence result in an independent cohort, it is suggested that further assessment of this region could be useful in determining response to atomoxetine in ADHD.

Use of atomoxetine in children and adolescents with ADHD

AbstractAtomoxetine is a non‐stimulant drug licensed for use in the treatment of attention deficit‐hyperactivity disorder (ADHD).Dr Banerjee describes a study that was carried out over a two‐year period in the three ADHD clinics in East Kent Hospitals NHS Trust to evaluate the current practice on the use of atomoxetine in ADHD in children and adolescents. Copyright © 2009 Wiley Interface Ltd

Atomoxetine for the Treatment of Pediatric Nocturnal Enuresis

Current treatments for pediatric nocturnal enuresis rely upon the use of behavioral interventions, such as enuresis alarms, and pharmacological interventions, such as antidiuretic hormone analogs, tricyclic antidepressants, and anticholinergics. However, a considerable number of patients do not respond fully to any of these interventions, in spite of optimal behavioral management and medication dosing. This report describes 4 children with attention deficit hyperactivity disorder (ADHD) comorbid with nocturnal enuresis. Each child was treated with atomoxetine for ADHD and experienced serendipitous resolution of enuresis.

Atomoxetine for the Treatment of Pediatric Nocturnal Enuresis

Current treatments for pediatric nocturnal enuresis rely upon the use of behavioral interventions, such as enuresis alarms, and pharmacological interventions, such as antidiuretic hormone analogs, tricyclic antidepressants, and anticholinergics. However, a considerable number of patients do not respond fully to any of these interventions, in spite of optimal behavioral management and medication dosing. This report describes 4 children with attention deficit hyperactivity disorder (ADHD) comorbid with nocturnal enuresis. Each child was treated with atomoxetine for ADHD and experienced serendipitous resolution of enuresis.

Extended Efficacy of Once-Daily Atomoxetine in ADHD

The efficacy of atomoxetine administered once daily (final dose 1.3 +/- 0.3 mg/kg; mean 44.5 mg per day; range 10-80 mg per day) in the morning was assessed throughout the day, including evening and early morning, in a total of 197 children, 6 to 12 years of age (71% male), diagnosed with attention-deficit/hyperactivity disorder (ADHD) (69% had combined subtype ADHD, and 35% had comorbid oppositional defiant disorder).

Atomoxetine treatment of attention-deficit/hyperactivity disorder.

To review the literature of the first nonstimulant approved for treatment of attention-deficit/hyperactivity disorder (ADHD). Primary literature and review articles were obtained through PubMed/MEDLINE (1966-February 2003). Literature evaluating atomoxetine in ADHD was selected. Animal data were excluded. Stimulants are currently first-line therapy for ADHD. However, their use raises several concerns including the potential for abuse and adverse effects. Atomoxetine introduces a new therapeutic drug class, selective norepinephrine-reuptake inhibitors, for ADHD management. This additional treatment option offers potential advantages over current therapies. Clinical trials demonstrate that atomoxetine is a safe and effective alternative for ADHD treatment in children and adults; however, its disadvantages may hinder it from becoming a first-line agent.

Atomoxetine Increases Extracellular Levels of Norepinephrine and Dopamine in Prefrontal Cortex of Rat: A Potential Mechanism for Efficacy in Attention Deficit/Hyperactivity Disorder

The selective norepinephrine (NE) transporter inhibitor atomoxetine (formerly called tomoxetine or LY139603) has been shown to alleviate symptoms in Attention Deficit/Hyperactivity Disorder (ADHD). We investigated the mechanism of action of atomoxetine in ADHD by evaluating the interaction of atomoxetine with monoamine transporters, the effects on extracellular levels of monoamines, and the expression of the neuronal activity marker Fos in brain regions. Atomoxetine inhibited binding of radioligands to clonal cell lines transfected with human NE, serotonin (5-HT) and dopamine (DA) transporters with dissociation constants (Ki) values of 5, 77 and 1451 nM, respectively, demonstrating selectivity for NE transporters. In microdialysis studies, atomoxetine increased extracellular (EX) levels of NE in prefrontal cortex (PFC) 3-fold, but did not alter 5-HTEX levels. Atomoxetine also increased DAEX concentrations in PFC 3-fold, but did not alter DAEX in striatum or nucleus accumbens. In contrast, the psychostimulant methylphenidate, which is used in ADHD therapy, increased NEEX and DAEX equally in PFC, but also increased DAEX in the striatum and nucleus accumbens to the same level. The expression of the neuronal activity marker Fos was increased 3.7-fold in PFC by atomoxetine administration, but was not increased in the striatum or nucleus accumbens, consistent with the regional distribution of increased DAEX. We hypothesize that the atomoxetine-induced increase of catecholamines in PFC, a region involved in attention and memory, mediates the therapeutic effects of atomoxetine in ADHD. In contrast to methylphenidate, atomoxetine did not increase DA in striatum or nucleus accumbens, suggesting it would not have motoric or drug abuse liabilities.