Does atomoxetine improve executive function, inhibitory control, and hyperactivity? Results from a placebo-controlled trial using quantitative measurement technology.

The primary objective of this study was to evaluate the efficacy of atomoxetine (ATX) on attention-deficit/hyperactivity disorder (ADHD)-related symptoms assessed as standard variables of a computer-based continuous performance test (cb-CPT) combined with a motion-tracking (MT) device. This was a 2-arm, 8-week, randomized, double-blind, placebo-controlled study in patients with ADHD (6-12 years). Therapy with ATX started with 0.5 mg/kg per day for 1 week, followed by 7 weeks on the target dosage of 1.2 mg/kg per day. Primary outcomes were cb-CPT/MT standard scores after 8 weeks using mixed models for repeated measurements. In addition, investigator-rated ADHD Rating Scale (ADHD-RS), Weekly Ratings of Evening and Morning Behavior (WREMB), and Clinical Global Impression - Severity-ADHD (CGI-S-ADHD) scores were assessed. Of 128 patients randomized, 125 were evaluated (ATX/placebo: 63/62). Baseline characteristics were comparable in both groups (overall, 80.2% boys; mean [SD] age, 9.0 [1.79] years; comorbid Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition diagnosis, 40.0% oppositional defiant disorder/conduct disorder; prior stimulant treatment, 24.8%; ADHD-RS total score, 36.99 [11.56]). At week 8, all cb-CPT/MT q-scores were significantly reduced versus placebo (all P < 0.001) with effect sizes (ESs) of reaction time (RT) variation (ES = 0.71), mean RT (ES = 0.41), number of microevents (ES = 1.00), commission error rate (ES = 0.50), distance of movement (ES = 0.90), area of movement (ES = 1.08), omission error rate (ES = 0.70), time active (ES = 0.69), motion simplicity (ES = 0.38), and normalized variance of RT (ES = 0.50). Secondary end points also improved significantly in favor of ATX: ADHD-RS (total score ES = 1.30, P < 0.001; hyperactivity/impulsivity subscore ES = 1.37, P < 0.001; inattention subscore ES = 1.07, P < 0.001), WREMB (total score ES = 1.00, P < 0.001; morning subscore ES = 0.59, P = 0.002; evening subscore ES = 1.02, P < 0.001), CGI-S-ADHD (ES = 1.11, P < 0.001). The results of this study show that ATX for 8 weeks significantly reduced ADHD-related symptoms as measured by the cb-CPT/MT.

Atomoxetine versus placebo in children and adolescents with attention-deficit/hyperactivity disorder and comorbid oppositional defiant disorder: a double-blind, randomized, multicenter trial in Germany.

OBJECTIVES: The primary objective of this study was to evaluate the efficacy of atomoxetine (ATX, target dose 1.2 mg/kg daily) on symptoms of oppositional defiant disorder (ODD) in children and adolescents with attention-deficit/hyperactivity disorder (ADHD). A secondary objective was to compare fast versus slow up-titration of ATX. METHODS: This was a 3-arm, 9-week, randomized, placebo-controlled, double-blind study in ADHD patients (6-17 years) with comorbid ODD (Diagnostic and Statistical Manual of Mental Disorders, 4th edition [DSM-IV] criteria A-C) or conduct disorder (CD). ATX-treatment arms were as follows-ATX-fast: 7 days 0.5 mg/kg, then 1.2 mg/kg; ATX-slow: 7 days each at 0.5 and 0.8 mg/kg, then 1.2 mg/kg. Primary outcome was the Swanson, Nolan, and Pelham Rating Scale-Revised (SNAP-IV) ODD-score after 9 weeks (Mixed Effects Model for Repeated Measures, ATX-up-titration groups pooled). RESULTS: In total, 181 patients were randomized, and 180 evaluated (ATX-fast/ATX-slow/placebo: 60/61/59). Baseline characteristics were comparable (84.4% boys; mean age 11.0 years; DSM-IV: 100% ADHD, 75.6% with combined type, 74.4% ODD, 24.4% CD; SNAP-IV ODD-scores, mean ± standard deviation 15.5 ± 4.35). At week 9, SNAP-IV ODD scores were significantly lower versus placebo in both ATX-groups (least square mean [95% confidence interval]: ATX-fast 8.6 [7.2;9.9]; ATX-slow 9.0 [7.7;10.3]; placebo 12.0 [10.6;13.5]; least square mean, ATX-pooled minus placebo: -3.2 [-5.0, -1.5], effect size: -0.69, p < 0.001). SNAP-IV ADHD-scores, CD symptoms (investigator-rated Attention-Deficit and Disruptive Behavior Disorders Instrument, disruptive behavior), Clinical Global Impressions-Severity, and individual treatment behaviors showed corresponding results. Post-hoc analyses indicated interrelationships between the medication effects on ADHD, ODD, and CD symptom scores. For ATX-slow, time to early dropout was significantly longer versus placebo (Hazard Ratio [95% confidence interval]: 3.57 [1.42;8.94]; p = 0.007). Clinically relevant adverse effects (fatigue, sleep disorders, nausea, and gastrointestinal complaints; weeks 1-3) were reported in 60.0% of ATX-fast, 44.3% of ATX-slow, and 18.6% of placebo group patients. CONCLUSIONS: ATX for 9 weeks significantly reduced symptoms of ODD/CD and ADHD; slower ATX-up-titration may be better tolerated.

Effect of atomoxetine on quality of life and family burden: results from a randomized, placebo-controlled, double-blind study in children and adolescents with ADHD and comorbid oppositional defiant or conduct disorder.

PURPOSE: To evaluate the effect of atomoxetine on quality of life (QoL) and family burden in children and adolescents with attention deficit/hyperactivity disorder (ADHD) and comorbid oppositional defiant (ODD) or conduct disorder (CD). METHODS: This secondary analysis was based on a randomized, double-blind, 9-week study of atomoxetine (target dose 1.2 mg/kg body weight) versus placebo. The study included 180 patients (atomoxetine 121, placebo 59), aged 6-17 years. QoL was measured using the KINDL-R questionnaire. The total score encompasses six dimensions (or subscales) measuring QoL in terms of "physical well-being", "emotional well-being", "self-esteem", "friends", "family", and "school". Family burden of illness was measured using the FaBel questionnaire. RESULTS: With atomoxetine, the KINDL-R total score improved significantly (P = 0.021) more than with placebo. This improvement also applied to the subscales except for "physical well-being" (opposite effect) and "school" (no effect). No significant treatment group differences were seen on the FaBel questionnaire. No differences were found between the fast and slow titration groups in terms of ADHD, ODD, and disruptive behavior severity. Furthermore, no such differences were observed for QoL and family burden. CONCLUSIONS: This study suggests positive effects of atomoxetine on quality of life, as measured by the KINDL-R scores on emotional well-being, self-esteem, friends and family, in children and adolescents with ADHD and comorbid ODD/CD. No significant treatment effects were seen on family burden, as measured by FaBel total score.

Autoimmunity and inflammation due to a gain-of-function mutation in phospholipase C gamma 2 that specifically increases external Ca2+ entry.

The identification of specific genetic loci that contribute to inflammatory and autoimmune diseases has proved difficult due to the contribution of multiple interacting genes, the inherent genetic heterogeneity present in human populations, and a lack of new mouse mutants. By using N-ethyl-N-nitrosourea (ENU) mutagenesis to discover new immune regulators, we identified a point mutation in the murine phospholipase Cg2 (Plcg2) gene that leads to severe spontaneous inflammation and autoimmunity. The disease is composed of an autoimmune component mediated by autoantibody immune complexes and B and T cell independent inflammation. The underlying mechanism is a gain-of-function mutation in Plcg2, which leads to hyperreactive external calcium entry in B cells and expansion of innate inflammatory cells. This mutant identifies Plcg2 as a key regulator in an autoimmune and inflammatory disease mediated by B cells and non-B, non-T haematopoietic cells and emphasizes that by distinct genetic modulation, a single point mutation can lead to a complex immunological phenotype.