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1.  Prognostic factors of improvement in health-related quality of life in atomoxetine-treated children and adolescents with attention-deficit/hyperactivity disorder, based on a pooled analysis 
The objective of this study is to identify prognostic factors of treatment response to atomoxetine in improvement of health-related quality of life (HR-QoL), measured by the Child Health and Illness Profile-Child Edition Parent Report Form (CHIP-CE PRF) Achievement and Risk Avoidance domains, in children and adolescents with attention-deficit/hyperactivity disorder (ADHD). Pooled data from 3 placebo-controlled trials and separate data from 3 open-label trials of atomoxetine in children and adolescents with ADHD were analyzed using logistic regression methods. Based on baseline impairment in the Achievement and/or Risk Avoidance domains (CHIP-CE PRF < 40 points), 2 subsamples of subjects were included. Treatment outcome was categorized as <5 points or ≥5 points increase in the CHIP-CE PRF Achievement and Risk Avoidance domains. Data of 190 and 183 subjects from the pooled sample, and 422 and 355 subjects from the open-label trials were included in the analysis of Achievement and Risk Avoidance domains. Baseline CHIP-CE subdomain scores proved to be the most robust prognostic factors for treatment outcome in both domains, based on data from the pooled sample of double-blind studies and from the individual open-label studies (odds ratios [OR] 0.74–1.56, p < 0.05; OR < 1, indicating a worse baseline score associated with worse odds of responding). Initial treatment response (≥25 % reduction in ADHD Rating Scale scores in the first 4–6 weeks) was another robust prognostic factor, based on data from the open-label studies (OR 2.99–6.19, p < 0.05). Baseline impairment in HR-QoL and initial treatment response can be early prognostic factors of atomoxetine treatment outcome in HR-QoL in children and adolescents with ADHD.
doi:10.1007/s12402-013-0119-5
PMCID: PMC3935101  PMID: 24142305
ADHD; Health-related quality of life; Atomoxetine; CHIP-CE; Response prediction
2.  Acute atomoxetine treatment of younger and older children with ADHD: A meta-analysis of tolerability and efficacy 
Background
Atomoxetine is FDA-approved as a treatment of attention-deficit/hyperactivity disorder (ADHD) in patients aged 6 years to adult. Among pediatric clinical trials of atomoxetine to date, six with a randomized, double-blind, placebo-controlled design were used in this meta-analysis. The purpose of this article is to describe and compare the treatment response and tolerability of atomoxetine between younger children (6–7 years) and older children (8–12 years) with ADHD, as reported in these six acute treatment trials.
Methods
Data from six clinical trials of 6–9 weeks duration were pooled, yielding 280 subjects, ages 6–7 years, and 860 subjects, ages 8–12 years with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV)-diagnosed ADHD. Efficacy was analyzed using the ADHD Rating Scale-IV (ADHD-RS), Conners' Parent Rating Scale-revised (CPRS-R:S), and the Clinical Global Impression of ADHD Severity (CGI-ADHD-S).
Results
Atomoxetine was superior to placebo in both age categories for mean (SD) change in ADHD-RS total, total T, and subscale scores; 3 CPRS-R:S subscales; and CGI-ADHD-S from baseline. Although there were no significant treatment differentials between the age groups for these efficacy measures, the age groups themselves, regardless of treatment, were significantly different for ADHD-RS total (younger: ATX = -14.2 [13.8], PBO = -4.6 [10.4]; older: ATX = -15.4 [13.2], PBO = -7.3 [12.0]; p = .001), total T (younger: ATX = -15.2 [14.8], PBO = -4.9 [11.2]; older: ATX = -16.4 [14.6], PBO = -7.9 [13.1]; p = .003), and subscale scores (Inattentive: younger: ATX = -7.2 [7.5], PBO = -2.4 [5.7]; older: ATX = -8.0 [7.4], PBO = -3.9 [6.7]; p = .043; Hyperactive/Impulsive: younger: ATX = -7.0 [7.2], PBO = -2.1 [5.4]; older: ATX = -7.3 [7.0], PBO = -3.4 [6.3]; p < .001), as well as the CGI-ADHD-S score (younger: ATX = -1.2 [1.3], PBO = -0.5 [0.9]; older: ATX = -1.4 [1.3], PBO = -0.7 [1.1]; p = .010). Although few subjects discontinued from either age group due to adverse events, a significant treatment-by-age-group interaction was observed for abdominal pain (younger: ATX = 19%, PBO = 6%; older: ATX = 15%, PBO = 13%; p = .044), vomiting (younger: ATX = 14%, PBO = 2%; older: ATX = 9%, PBO = 6%; p = .053), cough (younger: ATX = 10%, PBO = 6%; older: ATX = 3%, PBO = 9%; p = .007), and pyrexia (younger: ATX = 5%, PBO = 2%; older: ATX = 3%, PBO = 5%; p = .058).
Conclusion
Atomoxetine is an effective and generally well-tolerated treatment of ADHD in both younger and older children as assessed by three recognized measures of symptoms in six controlled clinical trials.
Trial Registration
Not Applicable.
doi:10.1186/1753-2000-2-25
PMCID: PMC2556311  PMID: 18793405
3.  Atomoxetine for the treatment of Attention-Deficit/Hyperactivity Disorder (ADHD) in children with ADHD and dyslexia 
Background
The objective of this study was to assess the effects of atomoxetine on treating attention-deficit/hyperactivity disorder (ADHD), on reading performance, and on neurocognitive function in youth with ADHD and dyslexia (ADHD+D).
Methods
Patients with ADHD (n = 20) or ADHD+D (n = 36), aged 10-16 years, received open-label atomoxetine for 16 weeks. Data from the ADHD Rating Scale-IV (ADHDRS-IV), Kaufman Test of Educational Achievement (K-TEA), Working Memory Test Battery for Children (WMTB-C), and Life Participation Scale for ADHD-Child Version (LPS-C) were assessed.
Results
Atomoxetine demonstrated significant improvement for both groups on the ADHDRS-IV, LPS-C, and K-TEA reading comprehension standard and composite scores. K-TEA spelling subtest improvement was significant for the ADHD group, whereas the ADHD+D group showed significant reading decoding improvements. Substantial K-TEA reading and spelling subtest age equivalence gains (in months) were achieved for both groups. The WMTB-C central executive score change was significantly greater for the ADHD group. Conversely, the ADHD+D group showed significant phonological loop score enhancement by visit over the ADHD group. Atomoxetine was well tolerated, and commonly reported adverse events were similar to those previously reported.
Conclusions
Atomoxetine reduced ADHD symptoms and improved reading scores in both groups. Conversely, different patterns and magnitude of improvement in working memory component scores existed between ADHD and ADHD+D patients. Though limited by small sample size, group differences in relation to the comparable changes in improvement in ADHD symptoms could suggest that brain systems related to the therapeutic benefit of atomoxetine in reducing ADHD symptoms may be different in individuals with ADHD+D and ADHD without dyslexia.
Trial Registration
Clinical Trial Registry: ClinicalTrials.gov: NCT00191048
doi:10.1186/1753-2000-3-40
PMCID: PMC2805604  PMID: 20003507
4.  Time courses of improvement and symptom remission in children treated with atomoxetine for attention-deficit/hyperactivity disorder: analysis of Canadian open-label studies 
Background
The relatively short durations of the initial pivotal randomized placebo-controlled trials involving atomoxetine HCl for the treatment of attention-deficit/hyperactivity disorder (ADHD) provided limited insight into the time courses of ADHD core symptom responses to this nonstimulant, selective norepinephrine reuptake inhibitor. The aim of this analysis was to evaluate time courses of treatment responses or remission, as assessed by attainment of prespecified scores on the ADHD Rating Scale-IV-Parent Version: Investigator Administered and Scored (ADHDRS-IV-PI) and the Clinical Global Impressions-ADHD-Severity (CGI-ADHD-S) scales, during up to 1 year of atomoxetine treatment in children with ADHD.
Methods
Using pooled data from three Canadian open-label studies involving 338 children ages 6-11 years with ADHD who were treated with atomoxetine for 3, 6 and 12 months, and survival analysis methods for interval-censored data, we estimated the time to: 1) improvement and robust improvement defined by ≥25% and ≥40% reductions from baseline ADHDRS-IV-PI total scores, respectively; and 2) remission using two definitions: a final score of ADHDRS-IV-PI ≤18 or a final score of CGI-ADHD-S ≤2.
Results
The median time to improvement was 3.7 weeks (~1 month), but remission of symptoms did not occur until a median of 14.3 weeks (~3.5 months) using the most stringent CGI-ADHD-S threshold. Probabilities of robust improvement were 47% at or before 4 weeks of treatment; 76% at 12 weeks; 85% at 26 weeks; and 96% at 52 weeks. Probabilities of remission at these corresponding time points were 30%, 59%, 77%, and 85% (using the ADHDRS-IV scale) and 8%, 47%, 67%, and 75% (using the CGI-ADHD-S scale). The change from atomoxetine treatment month 5 to month 12 of -1.01 (1.03) was not statistically significant (p = .33).
Conclusions
Reductions in core ADHD symptoms during atomoxetine treatment are gradual. Although approximately one-half of study participants showed improvement at 1 month of atomoxetine treatment, remission criteria were not met until about 3 months. Understanding the time course of children's responses to atomoxetine treatment may inform clinical decision making and also influence the durations of trials comparing the effects of this medication with other ADHD treatments.
Trial Registrations
clinicaltrials.gov: NCT00191633, NCT00216918, NCT00191880.
doi:10.1186/1753-2000-5-14
PMCID: PMC3120776  PMID: 21569378
Attention-deficit/hyperactivity disorder; atomoxetine; drug therapy; remission; response; treatment outcomes
5.  A modelled economic evaluation comparing atomoxetine with methylphenidate in the treatment of children with attention-deficit/hyperactivity disorder in Spain 
BMC Psychiatry  2009;9:15.
Background
Attention Deficit/Hyperactivity Disorder (ADHD) is a neurobehavioural disorder, affecting 3–6% of school age children and adolescents in Spain. Methylphenidate (MPH), a mild stimulant, had long been the only approved medication available for ADHD children in Spain. Atomoxetine is a non-stimulant alternative in the treatment of ADHD with once-a-day oral dosing. This study aims to estimate the cost-effectiveness of atomoxetine compared to MPH. In addition, atomoxetine is compared to 'no medication' for patient populations who are ineligible for MPH (i.e. having stimulant-failure experience or co-morbidities precluding stimulant medication).
Methods
An economic model with Markov processes was developed to estimate the costs and benefits of atomoxetine versus either MPH or 'no medication'. The incremental cost per quality-adjusted life-year (QALY) was calculated for atomoxetine relative to the comparators. The Markov process incorporated 14 health states, representing a range of outcomes associated with treatment options. Utility values were obtained from the utility valuation survey of 83 parents of children with ADHD. The clinical data were based on a thorough review of controlled clinical trials and other clinical literature, and validated by international experts. Costs and outcomes were estimated using Monte Carlo simulation over a 1-year duration, with costs estimated from the perspective of the National Health Service in Spain.
Results
For stimulant-naïve patients without contra-indications to stimulants, the incremental costs per QALY gained for atomoxetine were € 34 308 (compared to an immediate-release MPH) and € 24 310 (compared to an extended-release MPH). For those patients who have stimulant-failure experience or contra-indications to stimulants, the incremental costs per QALY gained of atomoxetine compared to 'no medication' were € 23 820 and € 23 323, respectively.
Conclusion
The economic evaluation showed that atomoxetine is an effective alternative across a range of ADHD populations and offers value-for money in the treatment of ADHD.
doi:10.1186/1471-244X-9-15
PMCID: PMC2674033  PMID: 19366449
6.  Atomoxetine for the treatment of attention-deficit/hyperactivity disorder in children and adolescents: a review 
Objective:
This review examines and summarizes the pharmacodynamic and pharmacokinetic properties, short- and longer-term efficacy, the moderating effect of comorbid disorders, as well as short- and long-term safety and tolerability of atomoxetine for the treatment of pediatric attention-deficit/hyperactivity disorder (ADHD).
Methods:
A systematic literature search was performed to review the extant literature on articles pertaining to the pharmacological treatment with atomoxetine in pediatric and/or adolescent ADHD.
Results:
There is an extensive literature on atomoxetine; over 4000 children have participated in clinical trials of atomoxetine, demonstrating its short- and longer-term efficacy. In addition, studies have examined the moderating effect of comorbid disorders on atomoxetine response, as well as atomoxetine’s therapeutic potential for other psychiatric conditions. Short- and longer-term safety and tolerability continue to be reported.
Conclusions:
Atomoxetine is indicated for both acute and maintenance/extended treatment of pediatric ADHD. Clinicians and families must be familiar with atomoxetine’s evidence base, including its profile of clinical response and its possible effectiveness in the presence of comorbidity.
PMCID: PMC2695220  PMID: 19557116
ADHD; atomoxetine; pediatric
7.  Psychometric properties of the quality of life scale Child Health and Illness Profile-Child Edition in a combined analysis of five atomoxetine trials 
Our aim was to evaluate the psychometric properties of the generic quality of life (QoL) scale Child Health and Illness Profile-Child Edition (CHIP-CE) by means of a combined analysis of atomoxetine clinical trials in children and adolescents with attention-deficit/hyperactivity disorder (ADHD). Individual patient-level data from five clinical trials were included in the combined analysis. Psychometric properties of the CHIP-CE were explored in terms of internal consistency and structure. Patients (n = 794) aged between 6 and 15 years (mean 9.7) with mean baseline ADHD Rating Scale of 41.8 ± 8.04 were included. On average, 0.7 (SD 2.23) items were missing for the whole CHIP-CE. The internal consistency of the CHIP-CE assessed by Cronbach’s alpha was good for all sub-domains at baseline and at endpoint. Considerable ceiling effects were only observed for the “restricted activity” sub-domain. No considerable floor effects were seen. The factor analysis supported the 12-factor solution for the sub-domains, but not the 5-factor solution for the domains. Our analyses were based on a large sample of non-US patients which allowed the measurement of clear changes in QoL over time. The results support that the CHIP-CE scale is psychometrically robust over time in terms of internal consistency and structure.
doi:10.1007/s12402-011-0066-y
PMCID: PMC3220810  PMID: 21986814
Attention-deficit disorder with hyperactivity; Quality of life; Psychometrics; Factor analysis
8.  A Double-Blind, Placebo-Controlled Study of Atomoxetine in Young Children With ADHD 
Pediatrics  2011;127(4):e862-e868.
OBJECTIVE:
To evaluate the efficacy and tolerability of atomoxetine for the treatment of attention-deficit/hyperactivity disorder (ADHD) in 5- and 6-year-old children.
METHODS:
This was an 8-week, double-blind, placebo-controlled randomized clinical trial of atomoxetine in 101 children with ADHD. Atomoxetine or placebo was flexibly titrated to a maximum dose of 1.8 mg/kg per day. The pharmacotherapist reviewed psychoeducational material on ADHD and behavioral-management strategies with parents during each study visit.
RESULTS:
Significant mean decreases in parent (P = .009) and teacher (P = .02) ADHD–IV Rating Scale scores were demonstrated with atomoxetine compared with placebo. A total of 40% of children treated with atomoxetine met response criteria (Clinical Global Impression–Improvement Scale indicating much or very much improved) compared with 22% of children on placebo, which was not significant (P = .1). Decreased appetite, gastrointestinal upset, and sedation were significantly more common with atomoxetine than placebo. Although some children demonstrated a robust response to atomoxetine, for others the response was more attenuated. Sixty-two percent of subjects who received atomoxetine were moderately, markedly, or severely ill according to the Clinical Global Impression–Severity Scale at study completion.
CONCLUSIONS:
To our knowledge, this is the first randomized controlled trial of atomoxetine in children as young as 5 years. Atomoxetine generally was well tolerated and reduced core ADHD symptoms in the children on the basis of parent and teacher reports. Reductions in the ADHD-IV Rating Scale scores, however, did not necessarily translate to overall clinical and functional improvement, as demonstrated on the Clinical Global Impression–Severity Scale and the Clinical Global Impression–Improvement Scale. Despite benefits, the children in the atomoxetine group remained, on average, significantly impaired at the end of the study.
doi:10.1542/peds.2010-0825
PMCID: PMC3387889  PMID: 21422081
ADHD; atomoxetine; child; pharmacotherapy
9.  Pharmacological treatment for attention deficit hyperactivity disorder: functional outcomes in children and adolescents from non-Western countries 
Drugs in Context  2013;2013:212260.
Objective:
Functional outcomes were measured over a 12-month period in children and adolescents with attention deficit hyperactivity disorder (ADHD) after they received monotherapy.
Design:
Prospective, observational, noninterventional study.
Setting:
Conducted in six non-Western countries.
Participants:
Outpatients 6 to 17 years of age with a verified diagnosis of ADHD in accordance with the Diagnostic and Statistical Manual, Fourth Edition, Text Revision (DSM-IV-TR), together with their physicians, decided to initiate or switch treatment for ADHD. Patients were prescribed pharmacological monotherapy: methylphenidate (n=221), nootropic agents (n=91), or atomoxetine (n=234).
Measurements:
Patients were followed for changes in their functional status and quality of life, which were assessed with the Child Health and Illness Profile–Child Edition (CHIP-CE) Achievement domain.
Results:
At the end of the study, a mean improvement on the CHIP-CE Achievement domain score was observed for all countries and therapies except in Taiwan, where patients received atomoxetine, and in Lebanon, where patients received methylphenidate. No patient experienced a serious adverse event during the study. Four patients discontinued due to a treatment-emergent adverse event.
Conclusion:
After 12 months of treatment, clinical and functional outcomes were improved in children and adolescents from non-Western countries who initiated and remained on their prescribed pharmacological monotherapy.
doi:10.7573/dic.212260
PMCID: PMC3884848  PMID: 24432046
atomoxetine; attention deficit hyperactivity disorder; adolescent; child; adverse drug events; treatment outcome; nootropic agents; central nervous system stimulants
10.  A randomized controlled trial investigation of a non-stimulant in attention deficit hyperactivity disorder (ACTION): Rationale and design 
Trials  2011;12:77.
Background
The 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.
Methods
Children 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.
Results
The methodology for the ACTION study has been detailed.
Conclusions
The 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 registration
Australian and New Zealand Clinical Trials Registry ANZCTRN12607000535471.
doi:10.1186/1745-6215-12-77
PMCID: PMC3068100  PMID: 21396130
11.  Randomized Controlled Trial of Atomoxetine for Cognitive Dysfunction in Early Huntington Disease 
Background
Cognitive symptoms are associated with functional disability in Huntington disease; yet, few controlled trials have examined cognitive treatments that could improve patient independence and quality of life. Atomoxetine is a norepinephrine reuptake inhibitor approved for treatment of attention-deficit/hyperactivity disorder.
Methods
Twenty participants with mild Huntington disease who complained of inattention were randomized to receive atomoxetine (80 mg/d) or placebo in a 10-week double-blind crossover study. Primary outcome measures were self-reported attention and attention and executive neuropsychological composite scores. Secondary outcomes were psychiatric and motor symptom scores.
Results
The rate of reported adverse effects while on atomoxetine was 56% (vs 35% on placebo), which most commonly included dry mouth (39%), loss of appetite (22%), insomnia (22%), and dizziness (17%). There were no serious adverse events related to atomoxetine. There were statistically significant, although mild, increases in heart rate and diastolic blood pressure on atomoxetine, consistent with other studies and not requiring medical referral. There were no significant improvements while on atomoxetine compared with placebo on primary outcomes. However, there was evidence of significant placebo effects on self-reported attention and psychiatric functions. There were no group differences on the Unified Huntington's Disease Rating total motor score.
Conclusions
Atomoxetine demonstrated no advantages over placebo for primary or secondary outcomes. Although atomoxetine was not effective at improving attention at this dose, its safety and tolerability were similar to other studies.
doi:10.1097/JCP.0b013e3181b2ac0a
PMCID: PMC3806326  PMID: 19745649
Huntington disease; randomized controlled trial; neuropsychological assessment; clinical trials
12.  A Placebo-Controlled Trial of Atomoxetine in Marijuana-Dependent Individuals with Attention Deficit Hyperactivity Disorder 
This study evaluated the effects of atomoxetine on the symptoms of attention deficit/hyperactivity disorder (ADHD) and marijuana use in marijuana-dependent adults. In conjunction with motivational interviewing, participants received either atomoxetine (n=19) or matching placebo (n=19) for 12 weeks. Participants randomized to atomoxetine had greater improvement in ADHD on the Clinical Global Impression-Improvement scale than participants treated with placebo. No treatment group differences in self-rated ADHD symptoms, overall Wender-Reimherr Adult Attention Deficit Disorder Scale scores, or marijuana use outcomes were noted. These results suggest that atomoxetine may improve some ADHD symptoms but does not reduce marijuana use in this population.
doi:10.1111/j.1521-0391.2010.00076.x
PMCID: PMC3019094  PMID: 20958842
13.  Atomoxetine improves patient and family coping in attention deficit/hyperactivity disorder: a randomized, double-blind, placebo-controlled study in Swedish children and adolescents 
This 10-week study assessed the efficacy of atomoxetine in combination with psychoeducation compared to placebo and psychoeducation in the improvement of Quality of Life in Swedish stimulant-naive children and adolescents with attention deficit/hyperactivity disorder. A total of 99 patients were treated with atomoxetine (49 patients) or placebo (50 patients) for 10 weeks and assessed regarding broader areas of functioning using the Quality of Life measures Child Health and Illness Profile-Child Edition (CHIP-CE), Family Strain Index [FSI; equivalent to the Family Burden of Illness Module used in the study], Appraisal of Stress in Child-Rearing (ASCR), Five to fifteen (FTF), “I think I am” (“Jag tycker jag är”), and Children’s Depression Rating Scale-Revised (CDRS-R) before and after the active treatment phase. Simultaneously, the patients’ parents participated in a 4-session psychoeducation program. A statistically significant difference in favor of atomoxetine was seen in the improvement from baseline to study endpoint for the CHIP-CE domains “Achievement” and “Risk avoidance”, for the FSI total score, for the ASCR section (I) domain “Child as a burden”, for all FTF domains except for “Language and Speech”, and for the CDRS-R total score. No difference between treatment groups was observed in the patient-assessed evaluation of self-esteem using the “I think I am” scale. Atomoxetine combined with psychoeducation had a positive effect on various everyday coping abilities of the patients as well as their families during 10 weeks of treatment, whereas the patients’ self-image and the parents’ image of the climate in the family were not significantly improved.
doi:10.1007/s00787-009-0031-x
PMCID: PMC2770135  PMID: 19466476
ADHD; Atomoxetine; Quality of life; CHIP-CE; Broader efficacy
14.  The epidemiology of pharmacologically treated attention deficit hyperactivity disorder (ADHD) in children, adolescents and adults in UK primary care 
BMC Pediatrics  2012;12:78.
Background
Attention Deficit Hyperactivity Disorder (ADHD) is a common neurodevelopmental disorder characterised by the symptoms of inattention, impulsivity and hyperactivity. ADHD was once perceived as a condition of childhood only; however increasing evidence has highlighted the existence of ADHD in older adolescents and adults. Estimates for the prevalence of ADHD in adults range from 2.5–4%. Few data exist on the prescribing trends of the stimulants methylphenidate and dexamfetamine, and the non-stimulant atomoxetine in the UK. The aim of this study was to investigate the annual prevalence and incidence of pharmacologically treated ADHD in children, adolescents and adults in UK primary care.
Methods
The Health Improvement Network (THIN) database was used to identify all patients aged over 6 years with a diagnosis of ADHD/hyperkinetic disorder and a prescription for methylphenidate, dexamfetamine or atomoxetine from 2003–2008. Annual prevalence and incidence of pharmacologically treated ADHD were calculated by age category and sex.
Results
The source population comprised 3,529,615 patients (48.9% male). A total of 118,929 prescriptions were recorded for the 4,530 patients in the pharmacologically treated ADHD cohort during the 6-year study. Prevalence (per 1000 persons in the mid-year THIN population) increased within each age category from 2003 to 2008 [6–12 years: from 4.8 (95% CI: 4.5–5.1) to 9.2 (95% CI: 8.8–9.6); 13–17 years: from 3.6 (95% CI: 3.3–3.9) to 7.4 (95% CI: 7.0–7.8); 18–24 years: from 0.3 (95% CI: 0.2–0.3) to 1.1 (95% CI: 1.0–1.3); 25–45 years: from 0.02 (95% CI: 0.01–0.03) to 0.08 (95% CI: 0.06–0.10); >45 years: from 0.01 (95% CI: 0.00–0.01) to 0.02 (95% CI: 0.01–0.03). Whilst male patients aged 6-12 years had the highest prevalence; the relative increase in prescribing was higher amongst female patients of the same age - the increase in prevalence in females aged 6–12 years was 2.1 fold compared to an increase of 1.9 fold for their male counterparts. Prevalence of treated ADHD decreased with increasing age. Incidence (per 1000 persons at risk in the mid-year THIN population) was highest for children aged 6–12 years.
Conclusions
A trend of increasing prescribing prevalence of ADHD drug treatment was observed over the period 2003–2008. Prevalence of prescribing to adult patients increased; however the numbers treated are much lower than published estimates of the prevalence of ADHD. This study has added to the limited knowledge on ADHD prescribing in primary care, particularly in the area of drug treatment in adulthood.
doi:10.1186/1471-2431-12-78
PMCID: PMC3472167  PMID: 22712630
15.  Relationship between atomoxetine plasma concentration, treatment response and tolerability in attention-deficit/hyperactivity disorder and comorbid oppositional defiant disorder 
The purpose of this study was to examine whether atomoxetine plasma concentration predicts attention-deficit/hyperactivity disorder (ADHD) or oppositional defiant disorder (ODD) response. This post-hoc analysis assessed the relationship between atomoxetine plasma concentration and ADHD and ODD symptoms in patients (with ADHD and comorbid ODD) aged 6–12 years. Patients were randomly assigned to atomoxetine 1.2 mg/kg/day (n = 156) or placebo (n = 70) for 8 weeks (Study Period II). At the end of 8 weeks, ODD non-remitters (score >9 on the SNAP-IV ODD subscale and CGI-I > 2) with atomoxetine plasma concentration <800 ng/ml at 2 weeks were re-randomized to either atomoxetine 1.2 mg/kg/day or 2.4 mg/kg/day for an additional 4 weeks (Study Period III). ODD remitters and non-remitters with plasma atomoxetine ≥800 ng/ml remained on 1.2 mg/kg/day atomoxetine for 4 weeks. Patients who received atomoxetine, completed Study Period II, and entered Study Period III were included in these analyses. All the groups demonstrated improvement on the SNAP-IV ODD and ADHD-combined subscales (P < .001). At the end of Study Periods II and III, ODD and ADHD improvement was significantly greater in the remitter group compared with the non-remitter groups. Symptom improvement was numerically greater in the non-remitter (2.4 mg/kg/day compared with the non-remitter 1.2 mg/kg/day) group. Atomoxetine plasma concentration was not indicative of ODD and ADHD improvement after 12 weeks of treatment. ADHD and ODD symptoms improved in all the groups with longer duration on atomoxetine. Results suggest atomoxetine plasma concentration does not predict ODD and ADHD symptom improvement. However, a higher atomoxetine dose may benefit some patients.
doi:10.1007/s12402-009-0012-4
PMCID: PMC2837233  PMID: 20234828
Atomoxetine; ADHD; Plasma concentration; ODD
16.  Effects of FDA Advisories on the Pharmacologic Treatment of ADHD, 2004–2008 
Objective
This study assessed the effect of public health advisories issued between 2005 and 2007 by the U.S. Food and Drug Administration (FDA) on treatments of attention-deficit hyperactivity disorder (ADHD) and physician prescribing practices.
Methods
Data obtained from the IMS Health National Disease and Therapeutic Index, a nationally representative audit of ambulatory physicians, were used to examine trends in office visits by children and adolescents (under age 18) during which ADHD was treated with Adderall, other psychostimulants, or atomoxetine. Segmented time series regressions were conducted to determine changes in use associated with three advisories issued between 2005 and 2007.
Results
In 2004, before the first FDA advisory, Adderall accounted for 36% of ADHD pharmacotherapy treatment visits. Other stimulants accounted for 46%, and atomoxetine accounted for 19%. Overall pharmacotherapy treatment rates were stable over the study period, but by 2008 the treatment visits accounted for by Adderall (that is, market share) declined to 24%, and the market share for atomoxetine declined to 8%. The market share for substitute therapies—clonidine, guanfacine, and bupropion—was stable over this period, ranging from 5% to 7%. Despite the declines in the use of Adderall and atomoxetine over the study period, results from the regression models suggest that the advisories did not have a statistically significant effect on ADHD medication prescribing.
Conclusions
FDA advisories regarding potential cardiovascular and other risks of ADHD medications had little discernible incremental effect on the use of these medicines in this nationally representative ambulatory audit.
doi:10.1176/appi.ps.201200147
PMCID: PMC4023684  PMID: 23318985
17.  Atomoxetine in Children and Adolescents with Attention-Deficit/Hyperactivity Disorder. Systematic Review of Review Papers 2009–2011. An Update for Clinicians 
Attention deficit/hyperactivity disorder (ADHD) is a common disorder and a plethora of new data has been published from clinical trials and national epidemiological databases in the last three years. In the United Kingdom Atomoxetine is currently the only licensed non-stimulant medication. As part of a systematic review of atomoxetine data Jan 2009–June 2011 formal searches found 750 citations. From these 13 met criteria for either review or systematic review papers and contained clinical data synthesis on atomoxetine. No individual review paper alone would be sufficient for clinicians to be updated at that time on all clinical aspects of atomoxetine data. The crucial data relating to clinical parity of atomoxetine and methylphenidate in trials and meta-analysis where relevant confounding biases are removed are not often discussed. Systematic review of complex data is critical for ADHD clinicians and will need regular updating due to the large volume of new data.
doi:10.4137/JCNSD.S4391
PMCID: PMC3663616  PMID: 23861650
ADHD; suicidality; summary of product characteristics; systematic review; review; atomoxetine
18.  Randomized, controlled trial of atomoxetine for ADHD in adolescents with substance use disorder 
Objective
To evaluate the effect of atomoxetine hydrochloride versus placebo on attention-deficit/hyperactivity disorder (ADHD) and substance use disorder (SUD) in adolescents receiving motivational interviewing / cognitive behavioral therapy (MI/CBT) for SUD.
Method
This single-site, randomized, controlled trial was conducted between December 2005 and February 2008. Seventy adolescents (13-19 years) with Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) (DSM-IV) ADHD, a DSM-IV ADHD checklist score greater than or equal to 22, and at least one non-tobacco SUD were recruited from the community. All subjects received 12 weeks of atomoxetine hydrochloride + MI/CBT versus placebo + MI/CBT. The main outcome measure for ADHD was self-report DSM-IV ADHD checklist score. For SUD, the main outcome was self-report number of days used non-tobacco substances in the past 28 days using the Timeline Followback interview.
Results
Change in ADHD scores did not differ between atomoxetine + MI/CBT and placebo + MI/CBT (F4,191 = 1.23, p = 0.2975). Change in days used non-nicotine substances in the last 28 days did not differ between groups (F3,100 = 2.06, p = 0.1103).
Conclusions
There was no significant difference between the atomoxetine + MI/CBT and placebo + MI/CBT groups in ADHD or substance use change. The MI/CBT and/or a placebo effect may have contributed to a large treatment response in the placebo group.
doi:10.1016/j.jaac.2010.02.013
PMCID: PMC2876346  PMID: 20494267
attention-deficit/hyperactivity disorder; adolescent; atomoxetine; substance use disorder
19.  Atomoxetine: a novel treatment for child and adult ADHD 
Attention deficit hyperactivity disorder (ADHD) is a common chronic condition with childhood onset that can continue into adulthood. Medication is a fundamental element in the management of this disorder. Atomoxetine is the newest nonstimulant medication approved by the United States Food and Drug Administration (FDA) for the treatment of ADHD. It is the only nonstimulant medication approved by the FDA for treatment of adult ADHD. Atomoxetine is a norepinephrine reuptake inhibitor that selectively inhibits the presynaptic norepinephrine transporter. A growing body of literature supports the use of atomoxetine both in children and adults with ADHD. This paper summarizes information from the literature about atomoxetine, including pharmacokinetics, pharmacodynamics, clinical trials, dosing, and side-effects.
PMCID: PMC2671957  PMID: 19412494
atomoxetine; ADHD; review; nonstimulants
20.  Emotional well-being in children and adolescents treated with atomoxetine for attention-deficit/hyperactivity disorder: Findings from a patient, parent and physician perspective using items from the pediatric adverse event rating scale (PAERS) 
Background
The objective of this analysis was to measure changes in items on the Pediatric Adverse Event Rating Scale (PAERS) that relate to emotional well-being of children and adolescents with Attention-Deficit/Hyperactivity Disorder (ADHD) during treatment with atomoxetine for up to 24 weeks from the perspective of the patient, the parent, and the physician.
Methods
Patients aged 6–17 years with ADHD were treated with atomoxetine (target dose 1.2 mg/kg/day). In the two studies on which this secondary analysis is based the PAERS was used to assess the tolerability of atomoxetine in children and adolescents. This scale has a total of 48 items. The ten items that reflect emotional well-being were selected to measure changes over time from a patient, parent, and physician perspective.
Results
421 patients were treated with atomoxetine. 355 patients completed the 8-week treatment period, and 260 patients completed the 24-week treatment period. The ten items that reflect emotional well-being were grouped in five dimensions: depressed mood, self-harm, irritability/agitation, drowsiness, and euphoria. The scores of these dimensions decreased over time, both from a patient as well as from a parent and physician perspective. Only the dimension self-harm was extremely low at baseline and stayed low over time. The mean scores for the ten items depended on the rater perspective.
Conclusion
The emotional well-being of children and adolescents with ADHD improved in terms of depressed mood, irritability/agitation, drowsiness, and euphoria during treatment with atomoxetine for up to 24 weeks.
doi:10.1186/1753-2000-2-11
PMCID: PMC2430545  PMID: 18507848
21.  Efficacy and Safety of Atomoxetine in the Treatment of Children and Adolescents with Attention Deficit Hyperactivity Disorder 
Several non-stimulant medications have been used in the treatment of attention deficit hyperactivity disorder (ADHD). Atomoxetine, was introduced in 2002. The safety and efficacy of atomoxetine in the treatment of ADHD for children, adolescents, and adults has been evaluated in over 4000 patients in randomized controlled studies and double blinded studies as well as in recent large longitudinal studies. This paper provides an updated summary of the literature on atomoxetine, particularly in relation to findings on the short- and long-term safety of atomoxetine in children and adolescents arising from recent large longitudinal cohort studies. Information is presented about the efficacy, safety, and tolerability of this medication.
doi:10.4137/CMPed.S7868
PMCID: PMC3620814  PMID: 23641171
atomoxetine; children; adolescents; ADHD; safety; efficacy
22.  Prospective, Naturalistic, Pilot Study of Open-Label Atomoxetine Treatment in Preschool Children with Attention-Deficit/Hyperactivity Disorder 
Abstract
Objective
The aim of this study was to report preliminary data regarding effectiveness and tolerability of atomoxetine in 3- to 5-year-old preschool children with attention-deficit/hyperactivity disorder (ADHD).
Methods
Nine boys and 3 girls (mean age = 5.0 ± 0.72 years) diagnosed with ADHD were treated with atomoxetine in an open-label pilot study. Atomoxetine was gradually titrated to a maximum dose of 1.8 mg/kg per day.
Results
There was a significant effect of time from baseline to end point on the parent-rated hyperactivity/impulsivity Swanson Nolan and Pelham (SNAP-IV-HI) subscale ratings (F[9, 11] = 6.32, p < 0.0001). The mean difference between the baseline and end-point parent SNAP-IV-HI scores was 10.2 ± 7.3 (p = 0.0005). The rate of positive response (defined as at least a 30% reduction in the end-point parent SNAP-IV-HI scores and a Clinical Global Impressions–Improvement [CGI-I] rating of Much Improved or Very Much Improved) was 75%. The Children's Global Assessment Scale scores improved significantly over time [F(9, 11) = 6.24 p < 0.001]. The mean end-point daily dose of atomoxetine was 1.59 ± 0.3 mg/kg. A high proportion (66.7%) of the preschoolers experienced side effects with atomoxetine. Side effects of defiance, tantrums, aggression, and irritability were most disconcerting to parents, and gastrointestinal complaints were the most commonly reported adverse effects. One child was terminated from the study due to “chest ache.” There were no changes in weight, height, or cardiovascular measures.
Conclusion
This open-label pilot study provides preliminary evidence of effectiveness and tolerability of atomoxetine for treating ADHD in preschool children, although double-blind, randomized, placebo-controlled studies are needed to confirm this.
doi:10.1089/cap.2008.054
PMCID: PMC2857147  PMID: 19364293
23.  Global impression of perceived difficulties in children and adolescents with attention-deficit/hyperactivity disorder: Reliability and validity of a new instrument assessing perceived difficulties from a patient, parent and physician perspective over the day 
Background
The objective of this analysis was to evaluate the psychometric properties of a brief scale developed to assess the degree of difficulties in children with Attention-Deficit/Hyperactivity Disorder (ADHD). The Global Impression of Perceived Difficulties (GIPD) scale reflects overall impairment, psychosocial functioning and Quality of Life (QoL) as rated by patient, parents and physician at various times of the day.
Methods
In two open-label studies, ADHD-patients aged 6–17 years were treated with atomoxetine (target-dose 0.5–1.2 mg/kg/day). ADHD-related difficulties were assessed up to week 24 using the GIPD. Data from both studies were combined to validate the scale.
Results
Overall, 421 patients received atomoxetine. GIPD scores improved over time. All three GIPD-versions (patient, parent, physician) were internally consistent; all items showed at least moderate item-total correlation. The scale showed good test-retest reliability over a two-week period from all three perspectives. Good convergent and discriminant validity was shown.
Conclusion
GIPD is an internally consistent, reliable and valid measure to assess difficulties in children with ADHD at various times of the day and can be used as indicator for psychosocial impairment and QoL. The scale is sensitive to treatment-related change.
doi:10.1186/1753-2000-2-10
PMCID: PMC2423352  PMID: 18507847
24.  Atomoxetine for the treatment of executive dysfunction in Parkinson’s disease 
Introduction
Executive dysfunction (ED) is a prominent and often disabling feature of cognitive impairment in Parkinson’s disease (PD). Few studies have examined treatments. Given the role of noradrenergic pathology in ED, atomoxetine, a norepinephrine reuptake inhibitor indicated for attention deficit hyperactivity disorder (ADHD), may be a potential treatment for PD-related ED.
Methods
12 patients with PD and disabling ED completed an 8-week pilot open-label, flexible dose (25 to 100 mg/day) trial of atomoxetine.
Results
On primary outcome measures, atomoxetine was associated with improved ED based on the Clinical Global Impression-Change Scale (75% positive response rate; 95% CI: 43%-95%, p<.05) and behavioral measures of ED [Frontal Systems Behavior Scale (FrSBE) Executive Dysfunction and Connors Adult ADHD Rating Scale (CAARS) inattention/memory subscales]. Adverse effects included sleep and gastrointestinal disturbances and hypomania.
Conclusion
Atomoxetine is tolerable in PD and may benefit clinical manifestations of ED, warranting further study in controlled trials.
doi:10.1002/mds.22307
PMCID: PMC2683743  PMID: 19025777
Executive Dysfunction; Parkinson’s disease; Cognition; Norepinephrine Reuptake inhibition; Atomoxetine
25.  Comparative efficacy and acceptability of methylphenidate and atomoxetine in treatment of attention deficit hyperactivity disorder in children and adolescents: a meta-analysis 
BMC Psychiatry  2011;11:176.
Background
Psychostimulants and non stimulants are effective in the treatment of ADHD. Efficacy of both methylphenidate and atomoxetine has been established in placebo controlled trials. Direct comparison of efficacy is now possible due to availability of results from several head-to-head trials of these two medications.
Methods
All published, randomized, open label or double blind trials, comparing efficacy of methylphenidate with atomoxetine, in treatment of ADHD in children, diagnosed using DSM-IV™ criteria were included. The outcome studied was ADHDRS-IVParent:Inv score. The standardized mean difference (SMD) was used as a measure of effect size.
Results
Nine randomized trials comparing methylphenidate and atomoxetine, with a total of 2762 participants were included. Meta-analysis did not find a significant difference in efficacy between methylphenidate and atomoxetine (SMD = 0.09, 95% CI -0.08-0.26) (Z = 1.06, p = 0.29). Synthesis of data from eight trials found no significant difference in response rates (RR = 0.93 95% CI 0.76-1.14, p = 0.49). Sub group analysis showed a significant standardized mean difference favouring OROS methylphenidate (SMD = 0.32, 95% CI 0.12-0.53 (Z = 3.05, p < 0.002). Immediate release methylphenidate was not superior to atomoxetine (SMD = -0.04, 95% CI -0.19-0.12) (Z = 0.46, p = 0.64). Excluding open label trials did not significantly alter the effect size (SMD = 0.08, 95% CI -0.04-0.21) (Z = 1.27, p = 0.20). All-cause discontinuation was used as a measure of acceptability. There was no significant difference in all cause discontinuation between atomoxetine and methylphenidate (RR 1.22, 95% CI 0.87-1.71). There was significant heterogeneity among the studies (p = 0.002, I2 = 67%). Subgroup analysis demonstrated the heterogeneity to be due to the open label trials (p = 0.001, I2 = 81%).
Conclusions
In general atomoxetine and methylphenidate have comparable efficacy and equal acceptability in treatment of ADHD in children and adolescents. However OROS methylphenidate is more effective than atomoxetine and may be considered as first line treatment in treatment of ADHD in children and adolescents.
doi:10.1186/1471-244X-11-176
PMCID: PMC3229459  PMID: 22074258

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