Esther Cardo

Evaluation of atomoxetine for first-line treatment of newly diagnosed, treatment-naïve children and adolescents with attention deficit/hyperactivity disorder.

Abstract Objective: To test the hypothesis that first-line treatment with atomoxetine provides superior efficacy than placebo for up to 12 weeks in improving the symptoms of Attention Deficit/Hyperactivity Disorder (ADHD). Research design and methods: This double-blind, randomized, placebo-controlled, parallel clinical trial included 151 treatment-naïve children (n = 113) and adolescents (n = 38) with newly diagnosed (≤3 months) ADHD. Atomoxetine dose was uptitrated from 0.5 to 1.2 mg/kg/day after two weeks. Outcome assessments included the ADHD Rating Scale-IV-Parent-reported Investigator-rated (ADHDRS-IV-Parent:Inv), the Clinical Global Impression of Severity of ADHD (CGI-ADHD-S), and the incidence of adverse events. Mixed-model repeated measures analysis was used to compare scale score changes between groups. Clinical trial registration: Trial registered at www.clinicaltrials.gov (study internal code: B4Z-XM-LYDM, identifier: NCT00191945). Results: Most patients were male (79.2%), of caucasian origin (96.0%) and severely ill (72.5%). Their mean age was 10.3 years. Atomoxetine-treated patients showed greater reductions from baseline to week 12 of total ADHDRS-IV-Parent:Inv score than placebo-treated patients (least square mean difference: −7.9 [95% CI: −11.0 to −4.8], corresponding to a large effect size of 0.8). Between-group mean differences increased progressively with treatment exposure from week 6 to 12 (−2.7 [−4.9 to −0.6] for total and −1.6 [−2.9 to −0.3] for inattention scores). At the end of the study, 50% of atomoxetine-treated patients (14% with placebo) showed a reduction ≥40% in total ADHDRS-IV-Parent:Inv score, and only 29% (46% with placebo) were severely ill (by CGI-ADHD-S). Treatment-related adverse events were significantly more frequent with atomoxetine (65.0%) than with placebo (37.3%), the most frequent being decreased appetite and somnolence. Only one case of decreased appetite was rated as severe. No patient discontinued treatment because of adverse events. Conclusions: A continued improvement of symptoms is expectable until 12 weeks in treatment-naïve ADHD patients treated with atomoxetine as first-line medication. Chief limitations are the small, national sample size and the absence of data beyond the 12-week time-point.

Changes of urine dihydroxyphenylglycol to norepinephrine ratio in children with attention-deficit hyperactivity disorder (ADHD) treated with atomoxetine.

This study investigated changes in the urine dihydroxyphenylglycol to norepinephrine ratio in patients with attention-deficit hyperactivity disorder (ADHD) treated with atomoxetine. The possible relationship with clinical response was also explored. Newly ADHD diagnosed, treatment-naïve children or adolescents were double-blindly randomized (2:1) to atomoxetine (n = 28) or placebo (n = 13). The dihydroxyphenylglycol to norepinephrine ratio decreased in both groups, showing significantly greater changes with atomoxetine than with placebo at week 6 (-42% versus -14%; P = .001), when dosed at 1.2 mg/kg/day, than at week 2 (-20% versus -2%; P = .118) with a dose of 0.5 mg/kg/day. Although the significant dihydroxyphenylglycol to norepinephrine ratio decrease with atomoxetine indicated norepinephrine transporter blockade, no association with ADHD clinical response (ADHD Rating Scale-IV-Parent:Investigator) was found. Therefore, dihydroxyphenylglycol to norepinephrine ratio might be a useful pharmacodynamic/pharmacokinetic biomarker, although not sufficiently sensitive to predict clinical efficacy. It remains a possibility that this ratio might have value to facilitate personalized atomoxetine pharmacotherapy in ADHD patients.

Evaluating internet information on attention-deficit/hyperactivity disorder (ADHD) treatment: Parent and expert perspectives

BACKGROUND The Internet is increasingly used as a source of health-related information. The objective of this study was to assess the quality of web-based information on treatments for attention-deficit/hyperactivity disorder (ADHD). METHODS Sixteen expert health professionals in ADHD and 35 parents of paediatric patients with a recent diagnosis of ADHD assessed the information contained in the 10 highest ranked websites in Spanish, using the Spanish version of the DISCERN tool - a validated questionnaire designed to assess the quality and reliability of web-based information on treatment choices (rating scores from 15 to 75). RESULTS DISCERN scores given by parents and experts were low (total mean scores [standard deviation]: 35.9 [13.1] and 43.4 [13.7], respectively) and inter-rater agreement was poor/moderate (weighted kappa for the global assessment between -0.69 and +0.93, average = 0.29). There was a significant change on the ADHD-knowledge and motivation for treatment (ADHD-KMT) basic knowledge sub-scale score after the assessment of the different websites by parents (total mean scores [standard deviation]: 49.09 [9.46] and 63.21 [9.45]). CONCLUSIONS Despite a poor/moderate inter-rater agreement between parent and expert opinions, all agreed that the quality of the web-based information on treatment choices for ADHD is generally poor.

Cluster-randomized, controlled 12-month trial to evaluate the effect of a parental psychoeducation program on medication persistence in children with attention-deficit/hyperactivity disorder

Background This multicenter, cluster-randomized, nonblinded study evaluated the effect of parental psychoeducation on medication persistence among children and adolescents with newly diagnosed attention-deficit/hyperactivity disorder (ADHD). Methods Patients received standard medication alone or medication plus a parental psychoeducation program, and were followed for 12 months. The primary endpoint was time to withdrawal or termination of medication due to any cause. Secondary endpoints included change in ADHD symptom severity, functional outcome, program satisfaction, and safety. Results A total of 208 patients completed the study, which was terminated early because recruitment had ceased. At 12 months, there was no significant difference between the psychoeducation and control groups in the proportion of patients who discontinued pharmacologic treatment (13.2% versus 14.3%, respectively; size effect −0.3, P=0.34; hazard ratio 0.72, 95% confidence interval 0.36–1.43). Psychoeducation was associated with a significantly greater improvement in ADHD symptoms but not in functional outcome. Parental satisfaction with psychoeducation was high, and satisfaction with pharmacologic treatment was significantly greater in the psychoeducation group. There were no safety concerns. Conclusion No significant advantage for parental psychoeducation plus medication over medication alone in terms of time to medication withdrawal was observed. Psychoeducation had inconsistent but interesting effects on other outcomes.

Fast vs. slow switching from stimulants to atomoxetine in children and adolescents with attention-deficit/hyperactivity disorder.

OBJECTIVE To compare fast versus slow switching from stimulants to atomoxetine (ATX) in children and adolescents with attention-deficit/hyperactivity disorder (ADHD). METHODS This was a randomized, controlled, open-label study in 6-16-year-old ADHD patients, previously treated with stimulants and cross-titrated (fast switch, over 2 weeks, or slow switch, over 10 weeks) to ATX because of unsatisfactory response and/or adverse events. Study duration was 14 weeks with an ATX standard target dose of 1.2 mg/kg/day. Primary measure was the change from baseline in the investigator-rated ADHD-Rating Scale (ADHD-RS) at weeks 2 and 10. Secondary measures included Global Impression of Perceived Difficulties (GIPD) and Child Health and Illness Profile-Child Edition (CHIP-CE). RESULTS The majority of the 111 patients were male (83.8%, n=93) and mean (SD) age was 11.5 (2.38) years. Mean baseline ADHD-RS total score was 36.0 in the fast and 38.0 in the slow group. Adjusted mean change after 2 weeks was -8.1 (-10.1; -6.1) in the fast and -8.0 (-9.9;-6.0) in the slow group (p=0.927), and after 10 weeks -15.0 (-17.4;-12.6) and -14.3 (-16.7;-12.0), respectively, (p=0.692). GIPD scores did not show differences between groups. Significant differences at week 10 were found in the CHIP-CE achievement domain favoring slow (p=0.036) and the comfort domain favoring fast cross-titration (p=0.030). No significant differences were found for adverse events, and differences for systolic blood pressure (BP) and weight were not considered clinically relevant. CONCLUSIONS ADHD-RS and GIPD scores improved in both switching groups. No clinically relevant differences between fast and slow switching from stimulants to ATX were found.

EPA-0775 – Efficacy of lisdexamfetamine dimesylate and atomoxetine in child and adolescent subgroups from a head-tohead, double-blind, randomized trial in patients with attention-deficit/hyperactivity disorder

Introduction Symptoms of attention-deficit/hyperactivity disorder (ADHD) appear in childhood and may persist into adolescence and beyond. Objective Evaluate the efficacy of lisdexamfetamine dimesylate (LDX) and atomoxetine in subgroups of children and adolescents with ADHD. Methods In this 9-week, double-blind study, patients aged 6–17 with ADHD and an inadequate response to previous methylphenidate therapy were randomized (1:1) to optimized doses of LDX or atomoxetine. Efficacy measures included ADHD Rating Scale IV (ADHD-RS-IV) total score and dichotomized Clinical Global Impressions-Improvement (CGI-I) score (improved, 1–2; not improved, 3–7). Results The full analysis set (n=262) comprised 194 children aged 6–12 (LDX, n=93; atomoxetine, n=101) and 68 adolescents aged 13–17 (LDX, n=34; atomoxetine, n=34). Mean optimized doses were: LDX, 52.5 (SD, 16.10) mg/day; atomoxetine, 40.2 (20.05) mg/day. Baseline mean ADHD-RS-IV total score was similar across treatment and age groups. Table shows efficacy results; safety profiles were consistent with previous studies. LDX Atomoxetine Mean change in ADHD-RS-IV total score by visit 9 (95% confidence interval) Overall −26.3 (−28.4, −24.2) −19.4 (−21.6, −17.2) Children −27.5 (−29.8, −25.1) −19.4 (−22.0, −16.7) Adolescents −22.9 (−27.3, −18.5) −19.5 (−23.7, −15.3) Patients (%) with improved CGI-I score by visit 9 (95% confidence interval) Overall 81.7 (75.0, 88.5) 63.6 (55.4, 71.8) Children 83.9 (76.4, 91.3) 61.2 (51.6, 70.9) Adolescents 75.8 (61.1, 90.4) 70.6 (55.3, 85.9) Conclusion Within each treatment group, improvements in symptomatological scales and global improvement ratings were observed in children and adolescents. Study funded by Shire .