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1.  Atomoxetine Improved Attention in Children and Adolescents with Attention-Deficit/Hyperactivity Disorder and Dyslexia in a 16 Week, Acute, Randomized, Double-Blind Trial 
Abstract
Objective
The purpose of this study was to evaluate atomoxetine treatment effects in attention-deficit/hyperactivity disorder (ADHD-only), attention-deficit/hyperactivity disorder with comorbid dyslexia (ADHD+D), or dyslexia only on ADHD core symptoms and on sluggish cognitive tempo (SCT), working memory, life performance, and self-concept.
Methods
Children and adolescents (10–16 years of age) with ADHD+D (n=124), dyslexia-only (n=58), or ADHD-only (n=27) received atomoxetine (1.0–1.4 mg/kg/day) or placebo (ADHD-only subjects received atomoxetine) in a 16 week, acute, randomized, double-blind trial with a 16 week, open-label extension phase (atomoxetine treatment only). Changes from baseline were assessed to weeks 16 and 32 in ADHD Rating Scale-IV-Parent-Version:Investigator-Administered and Scored (ADHDRS-IV-Parent:Inv); ADHD Rating Scale-IV-Teacher-Version (ADHDRS-IV-Teacher-Version); Life Participation Scale—Child- or Parent-Rated Version (LPS); Kiddie-Sluggish Cognitive Tempo (K-SCT) Interview; Multidimensional Self Concept Scale (MSCS); and Working Memory Test Battery for Children (WMTB-C).
Results
At week 16, atomoxetine treatment resulted in significant (p<0.05) improvement from baseline in subjects with ADHD+D versus placebo on ADHDRS-IV-Parent:Inv Total (primary outcome) and subscales, ADHDRS-IV-Teacher-Version Inattentive subscale, K-SCT Interview Parent and Teacher subscales, and WMTB-C Central Executive component scores; in subjects with Dyslexia-only, atomoxetine versus placebo significantly improved K-SCT Youth subscale scores from baseline. At Week 32, atomoxetine-treated ADHD+D subjects significantly improved from baseline on all measures except MSCS Family subscale and WMTB-C Central Executive and Visuo-spatial Sketchpad component scores. The atomoxetine-treated dyslexia-only subjects significantly improved from baseline to week 32 on ADHDRS-IV-Parent:Inv Inattentive subscale, K-SCT Parent and Teacher subscales, and WMTB-C Phonological Loop and Central Executive component scores. The atomoxetine-treated ADHD-only subjects significantly improved from baseline to Week 32 on ADHDRS-Parent:Inv Total and subscales, ADHDRS-IV-Teacher-Version Hyperactive/Impulsive subscale, LPS Self-Control and Total, all K-SCT subscales, and MSCS Academic and Competence subscale scores.
Conclusions
Atomoxetine treatment improved ADHD symptoms in subjects with ADHD+D and ADHD-only, but not in subjects with dyslexia-only without ADHD. This is the first study to report significant effects of any medication on SCT.
Clinical Trials Registration
This study was registered at: http://clinicaltrials.gov/ct2/home, NCT00607919.
doi:10.1089/cap.2013.0054
PMCID: PMC3842866  PMID: 24206099
2.  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
3.  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
4.  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
5.  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
6.  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
7.  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
8.  Correlates of alcohol use in adults with ADHD and comorbid alcohol use disorders: exploratory analysis of a placebo-controlled trial of atomoxetine 
Current medical research and opinion  2011;27(12):2309-2320.
Background
Attention-deficit/hyperactivity disorder (ADHD) and substance use disorder are often comorbid in adults. The effects of ADHD treatment on comorbid alcohol use disorder have not been extensively studied.
Objective
To assess correlates of ADHD and alcohol use outcomes in ADHD with comorbid alcohol use disorders, via a post-hoc exploratory subgroup analysis of a previously conducted, randomized, double-blind, placebo controlled study of recently abstinent adults.
Methods
Adults who had ADHD and alcohol use disorders and were abstinent for 4–30 days were randomized to daily atomoxetine 25–100 mg (mean final dose=89.9 mg) or placebo for 12 weeks. Changes in ADHD symptoms from baseline to endpoint were assessed using the ADHD Investigator Symptom Rating Scale (AISRS) total score, alcohol use by the timeline followback method, and alcohol cravings by the Obsessive Compulsive Drinking Scale.
Results
Of 147 subjects receiving atomoxetine (n=72) or placebo (n=75) in the primary study, 80 (54%) completed 12 weeks (n=32 atomoxetine; n=48 placebo). Improvements in ADHD symptoms on the AISRS correlated significantly with decreases in alcohol cravings (Pearson’s r=0.28; 95% confidence interval [CI]=0.11–0.43; p=0.002), and the correlation was most notable with atomoxetine (r=0.29; CI [0.04 – 0.51]; p=0.023) rather than with placebo (r=0.24; CI [0.00–0.46]; p=0.055). On-treatment drinking levels correlated with AISRS scores (r=0.12; CI [0.05 –0.19]; p=0.001). Relapse to alcohol abuse significantly correlated with worse ADHD symptoms on 15 of 18 items of the AISRS in the placebo group (p<0.05 for each).
Conclusions
No baseline predictor (other than degree of sobriety) of alcohol use or ADHD outcomes emerged. ADHD symptom improvements correlated significantly with reductions in alcohol cravings, and relapse to alcohol abuse correlated significantly with worsening of most ADHD symptoms in the placebo group, but not in the atomoxetine group. This post-hoc subgroup analysis is of a hypothesis-generating nature, and the generalizability of the findings may be limited by exclusion of adults with common ADHD comorbidities from the base study. Further, prospective clinical trials in larger and more heterogeneous patient populations are warranted to confirm or reject these preliminary associations.
doi:10.1185/03007995.2011.628648
PMCID: PMC3772672  PMID: 22029549
Adult; Alcohol; Atomoxetine; Attention-deficit/hyperactivity disorder; Drug therapy; Treatment outcomes
9.  ADHD in children and adolescents 
Clinical Evidence  2008;2008:0312.
Introduction
Prevalence estimates of attention deficit hyperactivity disorder (ADHD) vary according to the diagnostic criteria used and the population sampled. DSM-IV prevalence estimates among school children in the US are 3-5%, but other estimates vary from 1.7% to 16.0%. No objective test exists to confirm the diagnosis of ADHD, which remains a clinical diagnosis. Other conditions frequently co-exist with ADHD.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of pharmacological treatments for ADHD in children and adolescents? What are the effects of psychological treatments for ADHD in children and adolescents? What are the effects of combination treatments for ADHD in children and adolescents? We searched: Medline, Embase, The Cochrane Library, and other important databases up to June 2007 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 34 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review we present information relating to the effectiveness and safety of the following interventions: atomoxetine, bupropion, clonidine, dexamfetamine sulphate, homeopathy, methylphenidate, modafinil, omega 3-polyunsaturated fatty acids, and psychological/behavioural treatment (either alone or in combination with a drug treatment).
Key Points
Core symptoms of ADHD are inattention, hyperactivity, and impulsiveness, although other conditions frequently coexist with ADHD, including developmental disorders (especially motor, language, social communication, and specific learning disabilities) and psychiatric disorders (especially oppositional defiant and conduct disorder, anxiety, and depressive disorders). Symptoms must be present for at least 6 months, are generally observed in children before the age of 7 years, and cause clinically important impairment in social, academic, or occupational functioning which must be evident in more than one setting.Formal diagnostic criteria are most applicable to boys aged 6-12 years, and most research data relate to this group. Preschool children, adolescents, and females may present less-typical features, but similar levels of impairment. Prevalence estimates among school children range from 3% to 5%.
Methylphenidate improves core symptoms and school performance in children with ADHD when used alone.
Dexamfetamine and atomoxetine may also reduce symptoms of ADHD.
We don't know how effective any treatment for ADHD is in the long term; people with ADHD may require treatment for many years.
CAUTION: Atomoxetine may cause rare but serious liver injury.
Clonidine and modafinil may improve symptoms of ADHD compared with placebo, but are associated with an increased risk of adverse effects compared with methylphenidate, dexamfetamine, and atomoxetine.
We don't know whether homeopathy, bupropion, or polyunsaturated fatty acids are beneficial in the treatment of symptoms of ADHD.
We don't know how effective psychological/behavioural treatments alone are compared with each other or with pharmacological treatments, as we found few high-quality studies. The combination of methylphenidate plus psychological treatment may enhance effectiveness of methylphenidate alone or behavioural treatment alone, but we don't know whether dexamfetamine plus psychological treatment is effective in treatment of ADHD compared with either intervention alone. Long-term outcome for both drug treatment alone and combination treatments is uncertain.We don't know whether parent training in conjunction with teacher involvement is more effective than parent training alone.
PMCID: PMC2907929  PMID: 19445793
10.  ADHD in children and adolescents 
Clinical Evidence  2011;2011:0312.
Introduction
Prevalence estimates of attention deficit hyperactivity disorder (ADHD) vary according to the diagnostic criteria used and the population sampled. DSM-IV prevalence estimates among school children in the US are 3% to 5%, but other estimates vary from 1.7% to 16.0%. No objective test exists to confirm the diagnosis of ADHD, which remains a clinical diagnosis. Other conditions frequently co-exist with ADHD.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of pharmacological treatments for ADHD in children and adolescents? What are the effects of psychological treatments for ADHD in children and adolescents? What are the effects of combination treatments for ADHD in children and adolescents? We searched: Medline, Embase, The Cochrane Library, and other important databases up to August 2009 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 70 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review we present information relating to the effectiveness and safety of the following interventions: atomoxetine, bupropion, clonidine, dexamfetamine sulphate, homeopathy, methylphenidate, modafinil, omega-3 polyunsaturated fatty acids, and psychological/behavioural treatment (either alone or in combination with a drug treatment).
Key Points
Core symptoms of ADHD are inattention, hyperactivity, and impulsiveness, although other conditions frequently co-exist with ADHD, including developmental disorders (especially motor, language, social communication, and specific learning disabilities) and psychiatric disorders (especially oppositional defiant and conduct disorder, anxiety, and depressive disorders). Symptoms must be present for at least 6 months, are generally observed in children before the age of 7 years, and cause clinically important impairment in social, academic, or occupational functioning that must be evident in more than one setting.Formal diagnostic criteria are most applicable to boys aged 6 to 12 years, and most research data relate to this group. Pre-school children, adolescents, and females may present less typical features, but similar levels of impairment. Prevalence estimates among school children range from 3% to 5%.
Methylphenidate improves core symptoms in children with ADHD when used alone.
Dexamfetamine and atomoxetine may also reduce symptoms of ADHD.
We don't know how effective any treatment for ADHD is in the long term; people with ADHD may require treatment for many years.
CAUTION: Atomoxetine may cause rare but serious liver injury.
Clonidine and modafinil may improve symptoms of ADHD compared with placebo, but are associated with an increased risk of adverse effects compared with methylphenidate, dexamfetamine, and atomoxetine.
We don't know whether homeopathy, bupropion, or omega-3 polyunsaturated fatty acids are beneficial in the treatment of symptoms of ADHD.
We don't know how effective psychological/behavioural treatments alone are compared with each other or with pharmacological treatments, as we found few high-quality studies. The combination of methylphenidate plus psychological treatment may enhance effectiveness of methylphenidate alone or behavioural treatment alone, but we don't know whether dexamfetamine plus psychological treatment is effective in treatment of ADHD compared with either intervention alone. Long-term outcome for both drug treatment alone and combination treatments is uncertain.We don't know whether parent training in conjunction with teacher involvement is more effective than parent training alone.
PMCID: PMC3217800  PMID: 21718557
11.  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
12.  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
13.  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
14.  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
15.  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
16.  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
17.  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
18.  Atomoxetine for depression and other neuropsychiatric symptoms in Parkinson disease(LOE Classification) 
Neurology  2010;75(5):448-455.
Objectives:
Depression and antidepressant use, especially selective serotonin reuptake inhibitors (SSRIs), are common in Parkinson disease (PD). The objective of this clinical trial was to assess the efficacy of atomoxetine, a selective norepinephrine reuptake inhibitor (SNRI), for the treatment of clinically significant depressive symptoms and common comorbid neuropsychiatric symptoms in PD.
Methods:
A total of 55 subjects with PD and an Inventory of Depressive Symptomatology–Clinician (IDS-C) score ≥22 were randomized to 8 weeks of atomoxetine or placebo treatment (target dosage = 80 mg/day). Depression response (>50% decrease in IDS-C score or Clinical Global Impression–Improvement [CGI-I] score of 1 or 2) was assessed using intention-to-treat modeling procedures. Secondary outcomes included global cognition, daytime sleepiness, anxiety, apathy, and motor function.
Results:
There were no between-groups differences in a priori–defined response rates. Using a more liberal response criterion of >40% decrease in IDS score from baseline, there was a trend (p = 0.08) favoring atomoxetine. Patients receiving atomoxetine experienced significantly greater improvement in global cognition (p = 0.003) and daytime sleepiness (p = 0.001), and atomoxetine was well-tolerated.
Conclusions:
Atomoxetine treatment was not efficacious for the treatment of clinically significant depressive symptoms in PD, but was associated with improvement in global cognitive performance and daytime sleepiness. Larger studies of SNRIs in PD for disorders of mood, cognition, and wakefulness are appropriate.
Classification of evidence:
This interventional study provides Class II evidence that atomoxetine (target dosage = 80 mg/day) is not efficacious in improving clinically significant depression in PD.
GLOSSARY
= attention-deficit/hyperactivity disorder;
= Apathy Scale;
= Clinical Global Impression–Improvement;
= confidence interval;
= depression in Parkinson disease;
= Diagnostic and Statistical Manual of Mental Disorders, 4th edition;
= Epworth Sleepiness Scale;
= 15-item Geriatric Depression Scale;
= intraclass correlation coefficient;
= Inventory of Depressive Symptomatology–Clinician;
= locus ceruleus;
= Mini-Mental State Examination;
= number needed to treat;
= odds ratio;
= Parkinson disease;
= selective norepinephrine reuptake inhibitor;
= selective serotonin reuptake inhibitor;
= State Anxiety Inventory;
= tricyclic antidepressant;
= Unified Parkinson's Disease Rating Scale.
doi:10.1212/WNL.0b013e3181ebdd79
PMCID: PMC2918470  PMID: 20679638
19.  Treatment Response and Remission in a Double-Blind, Randomized, Head-to-Head Study of Lisdexamfetamine Dimesylate and Atomoxetine in Children and Adolescents with Attention-Deficit Hyperactivity Disorder 
CNS Drugs  2014;28(11):1059-1069.
Objectives
A secondary objective of this head-to-head study of lisdexamfetamine dimesylate (LDX) and atomoxetine (ATX) was to assess treatment response rates in children and adolescents with attention-deficit hyperactivity disorder (ADHD) and an inadequate response to methylphenidate (MPH). The primary efficacy and safety outcomes of the study, SPD489-317 (ClinicalTrials.gov NCT01106430), have been published previously.
Methods
In this 9-week, double-blind, active-controlled study, patients aged 6–17 years with a previous inadequate response to MPH were randomized (1:1) to dose-optimized LDX (30, 50 or 70 mg/day) or ATX (patients <70 kg: 0.5–1.2 mg/kg/day, not to exceed 1.4 mg/kg/day; patients ≥70 kg: 40, 80 or 100 mg/day). Treatment response was a secondary efficacy outcome and was predefined as a reduction from baseline in ADHD Rating Scale IV (ADHD-RS-IV) total score of at least 25, 30 or 50 %. Sustained response was predefined as a reduction from baseline in ADHD-RS-IV total score (≥25, ≥30 or ≥50 %) or a Clinical Global Impressions (CGI)–Improvement (CGI–I) score of 1 or 2 throughout weeks 4–9. CGI–Severity (CGI–S) scores were also assessed, as an indicator of remission.
Results
A total of 267 patients were enrolled (LDX, n = 133; ATX, n = 134) and 200 completed the study (LDX, n = 99; ATX, n = 101). By week 9, significantly (p < 0.01) greater proportions of patients receiving LDX than ATX met the response criteria of a reduction from baseline in ADHD-RS-IV total score of at least 25 % (90.5 vs. 76.7 %), 30 % (88.1 vs. 73.7 %) or 50 % (73.0 vs. 50.4 %). Sustained response rates were also significantly (p < 0.05) higher among LDX-treated patients (ADHD-RS-IV ≥25, 66.1 %; ADHD-RS-IV ≥30, 61.4 %; ADHD-RS-IV ≥50, 41.7 %; CGI–I, 52.0 %) than among ATX-treated individuals (ADHD-RS-IV ≥25, 51.1 %; ADHD-RS-IV ≥30, 47.4 %; ADHD-RS-IV ≥50, 23.7 %; CGI–I, 39.3 %). Finally, by week 9, 60.7 % of patients receiving LDX and 46.3 % of those receiving ATX had a CGI–S score of 1 (normal, not at all ill) or 2 (borderline mentally ill), and greater proportions of patients in the LDX group than the ATX group experienced a reduction from baseline of at least one CGI–S category.
Conclusions
Both LDX and ATX treatment were associated with high levels of treatment response in children and adolescents with ADHD and a previous inadequate response to MPH. However, within the parameters of the study, LDX was associated with significantly higher treatment response rates than ATX across all response criteria examined. In addition, higher proportions of patients in the LDX group than the ATX group had a CGI–S score of 1 or 2 by week 9, indicating remission of symptoms. Both treatments were generally well tolerated, with safety profiles consistent with those observed in previous studies.
doi:10.1007/s40263-014-0188-9
PMCID: PMC4221603  PMID: 25038977
20.  A Randomized, Open-Label Assessment of Response to Various Doses of Atomoxetine in Korean Pediatric Outpatients with Attention-Deficit/Hyperactivity Disorder 
Psychiatry Investigation  2011;8(2):141-148.
Objective
This multicenter, randomized, open-label, parallel trial aimed to provide a detailed dose-response profile for atomoxetine in Korean pediatric outpatients with attention-deficit/hyperactivity disorder (ADHD).
Methods
Male and female outpatients aged 6-18 years with ADHD meeting symptom severity criteria of 1.5 standard deviations above age and gender norms on the ADHD Rating Scale-IV-Parent: Investigator-Administered and Scored (ADHDRS-IV-Parent: Inv), and a Clinical Global Impression-ADHD-Severity score ≥4 were randomized to atomoxetine (mg/kg/day) 0.2 fixed, 0.5 fixed or 0.5 (7 days), 0.8 (7 days) then 1.2 for 28 days. The primary efficacy measure was change in ADHDRS-IV-Parent: Inv total score after 6 weeks of atomoxetine treatment.
Results
Of 153 randomized patients, 83.7% were male and mean age was 9.8 (SD±2.4) years. The completion rate was 86.9%. A graded dose response was apparent with mean change in ADHDRS-IV-Parent: Inv total scores of -9.6, -12.3 and -14.5 with atomoxetine 0.2, 0.5 and 1.2 mg/kg/day, respectively (p=0.024 - F-test). Moreover, a greater reduction in ADHD symptoms, as assessed by mean change from baseline to endpoint CGI-S and mean CGI-ADHD-Improvement at endpoint, was also observed with increasing atomoxetine dose. More patients receiving atomoxetine 1.2 mg/kg/day reported ≥1 treatment-emergent adverse event/s (58.3%) compared with 0.5 (40.7%; p=0.11) or 0.2 mg/kg/day (29.4%; p=0.005). These were generally mild to moderate.
Conclusion
Atomoxetine was found to be safe and well tolerated at all doses administered in Korean pediatric ADHD patients, and 1.2 mg/kg/day was an efficacious dose in this population.
doi:10.4306/pi.2011.8.2.141
PMCID: PMC3149109  PMID: 21852991
ADHD; Atomoxetine; Dose response; Korea; Pediatric
21.  Meta-Analysis: Treatment of Attention-Deficit/Hyperactivity Disorder in Children With Comorbid Tic Disorders 
Objective
The Food and Drug Administration currently requires the package inserts of most psychostimulant medications to list the presence of a tic disorder as a contraindication to their use. Approximately half of children with Tourette’s syndrome experience comorbid attention-deficit/hyperactivity disorder (ADHD). We sought to determine the relative efficacy of different medications in treating ADHD and tic symptoms in children with both Tourette’s syndrome and ADHD.
Method
We conducted a PubMed search to identify all double-blind, randomized, placebo-controlled trials examining the efficacy of medications in the treatment of ADHD in the children with comorbid tics. We used a random effects meta-analysis with standardized mean difference as our primary outcome to estimate the effect size of pharmaceutical agents in the treatment of ADHD symptoms and tics.
Results
Our meta-analysis included nine studies involving 477 subjects. We assessed the efficacy of six medications—dextroamphetamine, methylphenidate, alpha-2 agonists (clonidine and guanfacine), desipramine, atomoxetine, and deprenyl. Methylphenidate, alpha-2 agonists, desipramine, and atomoxetine demonstrated efficacy in improving ADHD symptoms in children with comorbid tics. Alpha-2 agonists and atomoxetine significantly improved comorbid tic symptoms. Although there was evidence that supratherapeutic doses of dextroamphetamine worsens tics, there was no evidence that methylphenidate worsened tic severity in the short term.
Conclusions
Methylphenidate seems to offer the greatest and most immediate improvement of ADHD symptoms and does not seem to worsen tic symptoms. Alpha-2 agonists offer the best combined improvement in both tic and ADHD symptoms. Atomoxetine and desipramine offer additional evidence-based treatments of ADHD in children with comorbid tics. Supratherapeutic doses of dextroamphetamine should be avoided.
doi:10.1097/CHI.0b013e3181b26e9f
PMCID: PMC3943246  PMID: 19625978
tic disorders; attention-deficit/hyperactivity disorder; methylphenidate; α2 adrenergic agonists; meta-analysis
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.  A pilot study for augmenting atomoxetine with methylphenidate: safety of concomitant therapy in children with attention-deficit/hyperactivity disorder 
Background
This study examined augmenting atomoxetine with extended-release methylphenidate in children whose attention-deficit/hyperactivity disorder (ADHD) previously failed to respond adequately to stimulant medication.
Methods
Children with ADHD and prior stimulant treatment (N = 25) received atomoxetine (1.2 mg/kg/day) plus placebo. After 4 weeks, patients who were responders (n = 4) were continued on atomoxetine/placebo while remaining patients were randomly assigned to either methylphenidate (ATX/MPH) (1.1 mg/kg/day) or placebo augmentation (ATX/PB) for another 6 weeks. Patients and sites were blind to timing of active augmentation. Safety measures included vital signs, weight, and adverse events. Efficacy was assessed by ADHD rating scales.
Results
Categorical increases in vital signs occurred for 5 patients (3 patients in ATX/MPH, 2 patients in ATX/PBO). Sixteen percent discontinued the study due to AE, but no difference between augmentation groups. Atomoxetine treatment was efficacious on outcome measures (P ≤ .001), but methylphenidate did not enhance response.
Conclusion
Methylphenidate appears to be safely combined with atomoxetine, but conclusions limited by small sample. With atomoxetine treatment, 43% of patients achieved normalization on ADHD ratings.
doi:10.1186/1753-2000-1-10
PMCID: PMC2098748  PMID: 17897473
24.  Atomoxetine affects transcription/translation of the NMDA receptor and the norepinephrine transporter in the rat brain – an in vivo study 
Attention-deficit/hyperactivity disorder (ADHD) is the most frequently diagnosed neurodevelopmental disorder. The norepinephrine transporter (NET) inhibitor atomoxetine, the first nonstimulant drug licensed for ADHD treatment, also acts as an N-methyl-D-aspartate receptor (NMDAR) antagonist. The compound’s effects on gene expression and protein levels of NET and NMDAR subunits (1, 2A, and 2B) are unknown. Therefore, adolescent Sprague Dawley rats were treated with atomoxetine (3 mg/kg, intraperitoneal injection [ip]) or saline (0.9%, ip) for 21 consecutive days on postnatal days (PND) 21–41. In humans, atomoxetine’s earliest clinical therapeutic effects emerge after 2–3 weeks. Material from prefrontal cortex, striatum (STR), mesencephalon (MES), and hippocampus (HC) was analyzed either directly after treatment (PND 42) or 2 months after termination of treatment (PND 101) to assess the compound’s long-term effects. In rat brains analyzed immediately after treatment, protein analysis exhibited decreased levels of the NET in HC, and NMDAR subunit 2B in both STR and HC; the transcript levels were unaltered. In rat brains probed 2 months after final atomoxetine exposure, messenger RNA analysis also revealed significantly reduced levels of genes coding for NMDAR subunits in MES and STR. NMDAR protein levels were reduced in STR and HC. Furthermore, the levels of two SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) proteins, synaptophysin and synaptosomal-associated protein 25, were also significantly altered in both treatment groups. This in vivo study detected atomoxetine’s effects beyond NET inhibition. Taken together, these data reveal that atomoxetine seems to decrease glutamatergic transmission in a brain region-specific manner. Long-term data show that the compound’s impact is not due to an acute pharmacological effect but lasts or even amplifies after a drug-free period of 2 months, leading to altered development of synaptic composition. These alterations might contribute to atomoxetine’s clinical effects in the treatment of ADHD, a neurodevelopmental disorder in which synaptic processes and especially a dysregulated glutamatergic metabolism seem to be involved.
doi:10.2147/DDDT.S50448
PMCID: PMC3857115  PMID: 24348020
attention-deficit hyperactivity disorder (ADHD); neurodevelopment; atomoxetine; in vivo study; altered gene expression; N-methyl-D-aspartate receptor
25.  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

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