Health-related quality of life in ADHD: a pooled analysis of gender differences in five atomoxetine trials

Attention-deficit/hyperactivity disorder (ADHD) is associated with considerable impairment in health-related quality of life (HR-QoL). Atomoxetine has been found to improve HR-QoL in both children and adolescents. However, there is scarcity of data on gender differences in treatment responses to ADHD medications. This pooled analysis of five atomoxetine trials aimed to evaluate treatment differences with respect to HR-QoL and ADHD symptoms across genders. Data from 5 clinical atomoxetine trials (4 from Europe and 1 from Canada) with similar inclusion and exclusion criteria and similar durations (8- to 12-week follow-up) were included in the pooled analysis. All studies included the Child Health and Illness Profile-Child Edition (CHIP-CE) Parent Report Form. In addition, correlations between HR-QoL and ADHD core symptoms were compared between girls and boys. Data from 136 girls and 658 boys (mean age: 9.6 and 9.7 years, respectively) were pooled. Boys and girls were similarly impaired at baseline with minor differences in some of the subdomains. Treatment effect of atomoxetine was significant in both groups for the Risk Avoidance domain and its subdomains. No gender effect with both clinical and statistical significance was found for treatment outcome. Correlations between ADHD Rating Scale and CHIP-CE scores were similar in both genders and were generally low at baseline and moderate at endpoint and for the change from baseline to endpoint. Atomoxetine was effective in improving some aspects of HR-QoL in both genders without any significant differences across genders. Correlations between core symptoms of ADHD and HR-QoL were low to moderate in both boys and girls.     

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.     

Adjunctive atomoxetine to SSRIs or SNRIs in the treatment of adult ADHD patients with comorbid partially responsive generalized anxiety (GA): an open-label study

To examine changes in partially responsive anxiety symptoms utilizing adjunctive treatment with atomoxetine in the treatment of adult ADHD patients with comorbid partially responsive anxiety symptoms. Consenting adult patients (n=29) with confirmed diagnosis of generalized anxiety and comorbid attention deficit hyperactivity disorder (ADHD) participated in this open-label study. All patients had significant comorbid anxiety symptoms (HAM-A>7) and failed to respond to 8-week trials of selective serotonin reuptake inhibitors (SSRIs) or noradrenaline reuptake inhibitors (SNRIs). All patients were treated with atomoxetine as adjunctive to SSRIs or to SNRIs and were followed for at least 12 weeks. The primary outcome measure was the Clinical Global Impression severity subscale. Other scales included the Hamilton Anxiety Scale (HAM-A), the adult ADHD Self-Report Scale (ASRS-v1.1) symptom checklist, and Sheehan's Disability Scale. Baseline measures prior to the treatment with atomoxetine were compared to those at 4, 8, and at 12 weeks of treatment. Monitoring for pulse, blood pressure, and weight changes was carried out at baseline and at end point. Twenty-seven patients (93%) completed this open-label study. There was significant resolution of symptoms of all outcome measures, including the symptoms of anxiety, as shown by changes from baseline in HAM-A, ASRS-v1.1, and CGI at 12 weeks (P<.001). Also, there was significant reduction in the disability score at 12 weeks. Patients completed the study, tolerated the adjunctive treatment, and there were no significant cardiovascular or weight changes. Two patients withdrew from the study during the first 4 weeks of treatment due to side effects. Atomoxetine can be used as an adjunctive treatment in adult patients with ADHD and comorbid partially responsive anxiety symptoms.     

Is emotion recognition the only problem in ADHD? effects of pharmacotherapy on face and emotion recognition in children with ADHD

The objectives of this study were to evaluate both face and emotion recognition, to detect differences among attention deficit and hyperactivity disorder (ADHD) subgroups, to identify effects of the gender and to assess the effects of methylphenidate and atomoxetine treatment on both face and emotion recognition in patients with ADHD. The study sample consisted of 41 male, 29 female patients, 8–15 years of age, who were diagnosed as having combined type ADHD (N = 26), hyperactive/impulsive type ADHD (N = 21) or inattentive type ADHD (N = 23) but had not previously used any medication for ADHD and 35 male, 25 female healthy individuals. Long-acting methylphenidate (OROS-MPH) was prescribed to 38 patients, whereas atomoxetine was prescribed to 32 patients. The reading the mind in the eyes test (RMET) and Benton face recognition test (BFRT) were applied to all participants before and after treatment. The patients with ADHD had a significantly lower number of correct answers in child and adolescent RMET and in BFRT than the healthy controls. Among the ADHD subtypes, the hyperactive/impulsive subtype had a lower number of correct answers in the RMET than the inattentive subtypes, and the hyperactive/impulsive subtype had a lower number of correct answers in short and long form of BFRT than the combined and inattentive subtypes. Male and female patients with ADHD did not differ significantly with respect to the number of correct answers on the RMET and BFRT. The patients showed significant improvement in RMET and BFRT after treatment with OROS-MPH or atomoxetine. Patients with ADHD have difficulties in face recognition as well as emotion recognition. Both OROS-MPH and atomoxetine affect emotion recognition. However, further studies on the face and emotion recognition are needed in ADHD.     

Minor differences in ADHD-related difficulties between boys and girls treated with atomoxetine for attention-deficit/hyperactivity disorder

Atomoxetine may improve ADHD-related difficulties and hence the quality of life (QoL) in children and adolescents. Perception of these difficulties may differ with the rater perspective (patient, parent, physician) or patients' sex. The objective of this study was to investigate QoL as reflected by perceived ADHD-related difficulties perceived from these three perspectives and compare boys and girls. Patients aged 6-17 with ADHD were treated with atomoxetine (target dose 0.5-1.2 mg/kg/day) in two studies. In both studies, ADHD-related difficulties were assessed after 8 and 24 weeks using the Global Impression of Perceived Difficulties (GIPD) instrument, which can be taken to reflect the patient's QoL from the three perspectives. Data from the two studies were combined and analyzed together in order to compare boys and girls. Four hundred and twenty-one patients were treated with atomoxetine, 338 boys and 83 girls. Three hundred and fifty-five patients completed the 8-week study period. QoL, as reflected by perceived ADHD-related difficulties (measured with GIPD), improved over time. Mean GIPD total scores showed a similar course over time for all rater groups, although the patients rated the degree of difficulties significantly lower than parents and physicians. The sexes did not differ significantly in mean GIPD total scores. The GIPD scores over time suggest that patients' QoL, as reflected by perceived ADHD-related difficulties, improved with time on atomoxetine. However, improvement did not differ significantly between boys and girls. Trial Registration: ClinicalTrials.gov Identifiers NCT00191516 and NCT00191737.     

Assessment of effects of atomoxetine in adult patients with ADHD: consistency among three geographic regions in a response maintenance study

A previous study (Upadhyaya et al. in Eur J Psychiatry 2013b; 27:185–205) reported that adults with attention-deficit/hyperactivity disorder (ADHD) demonstrated maintenance of response for up to 25 weeks after initially responding to atomoxetine treatment. In the present report, the consistency of treatment effect across three geographic regions (Europe, United States/Canada [US/Can], and Latin America [Latin Am]) was explored. Data were analyzed from a phase 3, multicenter, randomized, double-blind, maintenance-of-response (randomized withdrawal) trial of atomoxetine versus placebo in adults with ADHD. Patients were randomized to atomoxetine (N = 266) or placebo (N = 258) for 25 weeks. Consistency assessments included the interaction test, pairwise t tests, noninferiority, and the criteria from Basic Principles on Global Clinical Trials (Ministry of Health, Labour and Welfare of Japan 2007). Atomoxetine-treated patients maintained the improved ADHD symptoms relative to placebo-treated patients on the Conners’ Adult ADHD Rating Scale Investigator-Rated: Screening Version 18-Item (CAARS-Inv:SV) total score in all three regions (atomoxetine–placebo mean difference = ?4.55, ?3.18, and ?0.07 for Europe, US/Can, and Latin Am, respectively). For the Latin Am region, the mean change in total score (0.41) was notably smaller for the placebo group than for Europe (5.87) and US/Can (4.39). Similar results were observed for the CAARS-Inv:SV hyperactivity/impulsivity and inattention subscale scores. Overall, patients maintained the response with atomoxetine treatment compared to placebo; however, the magnitude of treatment effect differed among the regions studied, being numerically higher in the EU and US/Can than Latin Am. Trial registration http://www.clinicaltrials.gov/(NCT00700427).     

A new high performance liquid chromatographic method for quantification of atomoxetine in human plasma and its application for pharmacokinetic study

Atomoxetine is the first, non-stimulant alternative to other stimulant medications used for the treatment of Attention-Deficit/Hyperactivity Disorder (ADHD). Reported methods for the determination of atomoxetine include expensive liquid chromatography tandem mass spectrometry (LCMS) and high performance liquid chromatography (HPLC) with liquid scintillation counting (LSC) detection. Till date, no method has been reported in literature to determine atomoxetine using HPLC with UV detection. In this paper, we describe a new HPLC method for the determination of atomoxetine using liquid-liquid extraction with tertiary butyl methyl ether and UV detector. This method was found to be linear over the concentration range of 0.05-3.0 microg/ml. The limit of quantification was 0.05 microg/ml. Intra- and inter-day precision was <15% and accuracy was in the range of 95.67-108.80%. Stability studies showed that atomoxetine was stable in human plasma for short- and long-term period for sample preparation and analysis. This method was used for sample analysis in a pharmacokinetic study of atomoxetine (25mg) in five healthy adult female volunteers. The observed mean+/-S.D. pharmacokinetic parameters Cmax, Tmax and AUC(0-t) were 0.40+/-0.06 microg/ml, 3.40+/-0.42 h and 1.34+/-0.52 microg h/ml, respectively.     

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.     

Psychoeducational groups for youth attention-deficit hyperactivity disorder: a family medicine pilot project

Attention-deficit hyperactivity disorder (ADHD) is the most commonly diagnosed behavioural disorder of youth and is estimated to affect ～4% of school-age children. Although medication is the most common and efficacious treatment for ADHD, some experts believe that multimodal treatment strategies help children improve symptoms more than medicine alone. Psychoeducational strategies focus on educating youth and families about a given disorder. This study compared youth who participated with their parents in a five-session, one-hour psychoeducational group at a family medicine clinic and those who received customary treatment and were on a waiting list for the intervention. Findings of youth behaviour from parent and teacher perspectives were compared at the outset of the group and one month after group completion using the Vanderbilt scales. Results revealed that youth in both conditions improved over the two months of the study from the parent perspective in terms of all ADHD symptoms (e.g. inattention, hyperactivity/impulsivity) and in terms of school functioning. However, no gains were made in youth functioning or ADHD behaviour from the teacher perspective. Youth in the treatment group made modest gains in school performance from the parent perspective when compared with youth in the control condition. The results suggest that parents of ADHD youth should be involved in the treatment process to maximise the likelihood of improvement. Psychoeducational groups can be of modest benefit to help educate parents and youth regarding the challenges of ADHD management.     

Atomoxetine Effects on Executive Function as Measured by the BRIEF-A in Young Adults with ADHD: A Randomized,Double-Blind,Placebo-Controlled Study

Objective

To evaluate the effect of atomoxetine treatment on executive functions in young adults with attention-deficit/hyperactivity disorder (ADHD).

Methods

In this Phase 4, multi-center, double-blind, placebo-controlled trial, young adults (18–30 years) with ADHD were randomized to receive atomoxetine (20–50 mg BID, N = 220) or placebo (N = 225) for 12 weeks. The Behavior Rating Inventory of Executive Function-Adult (BRIEF-A) consists of 75 self-report items within 9 nonoverlapping clinical scales measuring various aspects of executive functioning. Mean changes from baseline to 12-week endpoint on the BRIEF-A were analyzed using an ANCOVA model (terms: baseline score, treatment, and investigator).

Results

At baseline, there were no significant treatment group differences in the percentage of patients with BRIEF-A composite or index T-scores ≥60 (p>.5), with over 92% of patients having composite scores ≥60 (≥60 deemed clinically meaningful for these analyses). At endpoint, statistically significantly greater mean reductions were seen in the atomoxetine versus placebo group for the BRIEF-A Global Executive Composite (GEC), Behavioral Regulation Index (BRI), and Metacognitive Index (MI) scores, as well as the Inhibit, Self-Monitor, Working Memory, Plan/Organize and Task Monitor subscale scores (p<.05), with decreases in scores signifying improvements in executive functioning. Changes in the BRIEF-A Initiate (p = .051), Organization of Materials (p = .051), Shift (p = .090), and Emotional Control (p = .219) subscale scores were not statistically significant. In addition, the validity scales: Inconsistency (p = .644), Infrequency (p = .097), and Negativity (p = .456) were not statistically significant, showing scale validity.

Conclusion

Statistically significantly greater improvement in executive function was observed in young adults with ADHD in the atomoxetine versus placebo group as measured by changes in the BRIEF-A scales.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00510276","term_id":"NCT00510276"}}NCT00510276     

Atomoxetine treatment for children and adolescents with Attention-Deficit/Hyperactivity Disorder (ADHD): a comprehensive meta-analysis of outcomes on parent-rated core symptomatology

Attention-Deficit/Hyperactivity Disorder (ADHD) impacts a significant number of children and adolescents and often leads to deleterious functional impairment. Psychostimulant medication has historically been the first line of pharmacological intervention, though recent years have seen greater attention paid to non-stimulant alternatives. The objective of the present study was to conduct the most comprehensive meta-analysis to date evaluating the efficacy of atomoxetine in reducing core symptomatology of ADHD according to parent report. Selection criteria were applied, and studies were located by searching electronic databases, review of reference sections, and contact with expert researchers; article searching began on 10/01/2013, and the final search was conducted on 09/01/2014. A total of 42 studies met inclusion criteria—33 with control groups and 9 without—for a total sample of 8398 individuals. For those receiving atomoxetine, the summary pre–post (e.g., standardized mean gain) effect size estimate was 1.37 (95% CI [1.24, 1.51], p < .001); atomoxetine was found to statistically significantly outperform control conditions overall (Z = 4.07, p < .001), though results differed by the type of control group; for instance, when comparing atomoxetine to alternative medications as controls, significant differences were no longer present. The non-stimulant atomoxetine led to significant improvement in core ADHD symptomatology and should be considered as a viable pharmacological treatment option for ADHD.     

Comorbid ADHD and mental health disorders: are these children more likely to develop reading disorders?

While attention-deficit/hyperactivity disorder (ADHD) has been associated with both internalizing and externalizing childhood behaviour disorders, the specific relationship of these comorbid disorders to ADHD and reading problems is less well defined. The present study analysed data from the Australian Twin ADHD Project, which utilized DSM-IV-based ratings of ADHD, separation anxiety disorder, generalized anxiety disorder, depression, conduct disorder, and oppositional defiant disorder for twins and siblings aged 6 to 18 years. While differences between children with and without ADHD were demonstrated for those with separation anxiety disorder, generalized anxiety disorder, depression, conduct disorder, oppositional defiant disorder and a reading disorder, for all age groups, regression analysis of ADHD diagnostic subtypes by age and reading disorder showed that only generalized anxiety disorder remained significant after controlling for ADHD subtypes. Analysis of the mean reading disorder scores in children with and without ADHD showed that children with conduct disorder had significantly more reading problems, as did children with multiple comorbid disorders. In summary, both age and ADHD diagnosis were associated with variations in these comorbid disorders, and multiple comorbid disorders were associated with greater reading impairment.     

Effects of atomoxetine on attention in Wistar rats treated with the neurotoxin <Emphasis Type="Italic">N</Emphasis>-(2-chloroethyl)-<Emphasis Type="Italic">N</Emphasis>-ethyl-2-bromobenzylamine (DSP4)

The aim of the present study was to assess the effects of the neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP4), which allows a depletion of noradrenergic terminals in a dose-dependent manner, on attention in rats as measured using the five-choice serial-reaction time task (5CSRTT). In addition, we investigated whether the effects of DSP4 treatment can be reversed by atomoxetine. Atomoxetine is a selective noradrenaline reuptake inhibitor and has been shown to be effective in the treatment of attention deficit hyperactivity disorder. Wistar rats were trained in the 5CSRTT and treated with one of the three doses of DSP4 (10, 20 or 50 mg/kg) or saline. Following DSP4 treatment, rats were injected with three doses of atomoxetine (0.1, 0.5 or 1 mg/kg) or saline and tested in the 5CSRTT. The treatment with DSP4 caused a reduction in activity and a decline of performance in parameters related to attention in the 5CSRTT. Whether or not these impairments are due to attention deficits or changes in explorative behaviour and activity remains to be investigated. The treatment with atomoxetine had no beneficial effect on the rats’ performance regardless of the DSP4 treatment. The present findings support the role of noradrenaline in modulating attentional processes and call for future studies regarding the effects of atomoxetine on attention in rats.     

注意缺陷多动障碍儿童睡眠障碍与铁缺乏关系的临床研究

目的：探讨注意缺陷多动障碍（ADHD）患儿睡眠障碍与血清铁蛋白水平的关系。方法：符合美国精神疾病诊断与统计手册第4版（DSM-Ⅳ）中ADHD诊断标准的62例6．14岁ADHD患儿,由ADHD患儿的父母填写睡眠障碍量表（SDSC）,检测ADH-D患儿的血清铁蛋白水平。结果：与血清铁蛋白水平高于45／μg／L的ADHD患儿相比较,血清铁蛋白水平低于45／μg／L的ADHD患儿的SDSC“睡眠醒觉转换障碍”项评分和总分明显高于前者（P〈0．05）。2组间其他项评分比较无显著性差异（P〉0．05）。SDSC“睡眠醒觉转换障碍”项评分与血清铁蛋白水平成负相关（P〈0．05）。结论：血清铁蛋白水平低于451μg／LADHD患儿SDSC“睡眠醒觉转换障碍”（睡眠中的异常运动）的危险性显著增加。     

Exploring the Validity of Proposed Transgenic Animal Models of Attention-Deficit Hyperactivity Disorder (ADHD)

Attention-deficit/hyperactivity disorder (ADHD) is a common, behavioral, and heterogeneous neurodevelopmental condition characterized by hyperactivity, impulsivity, and inattention. Symptoms of this disorder are managed by treatment with methylphenidate, amphetamine, and/or atomoxetine. The cause of ADHD is unknown, but substantial evidence indicates that this disorder has a significant genetic component. Transgenic animals have become an essential tool in uncovering the genetic factors underlying ADHD. Although they cannot accurately reflect the human condition, they can provide insights into the disorder that cannot be obtained from human studies due to various limitations. An ideal animal model of ADHD must have face (similarity in symptoms), predictive (similarity in response to treatment or medications), and construct (similarity in etiology or underlying pathophysiological mechanism) validity. As the exact etiology of ADHD remains unclear, the construct validity of animal models of ADHD would always be limited. The proposed transgenic animal models of ADHD have substantially increased and diversified over the years. In this paper, we compiled and explored the validity of proposed transgenic animal models of ADHD. Each of the reviewed transgenic animal models has strengths and limitations. Some fulfill most of the validity criteria of an animal model of ADHD and have been extensively used, while there are others that require further validation. Nevertheless, these transgenic animal models of ADHD have provided and will continue to provide valuable insights into the genetic underpinnings of this complex disorder.     

A Brain-Computer Interface Based Attention Training Program for Treating Attention Deficit Hyperactivity Disorder

Attention deficit hyperactivity disorder (ADHD) symptoms can be difficult to treat. We previously reported that a 20-session brain-computer interface (BCI) attention training programme improved ADHD symptoms. Here, we investigated a new more intensive BCI-based attention training game system on 20 unmedicated ADHD children (16 males, 4 females) with significant inattentive symptoms (combined and inattentive ADHD subtypes). This new system monitored attention through a head band with dry EEG sensors, which was used to drive a feed forward game. The system was calibrated for each user by measuring the EEG parameters during a Stroop task. Treatment consisted of an 8-week training comprising 24 sessions followed by 3 once-monthly booster training sessions. Following intervention, both parent-rated inattentive and hyperactive-impulsive symptoms on the ADHD Rating Scale showed significant improvement. At week 8, the mean improvement was −4.6 (5.9) and −4.7 (5.6) respectively for inattentive symptoms and hyperactive-impulsive symptoms (both p<0.01). Cohen’s d effect size for inattentive symptoms was large at 0.78 at week 8 and 0.84 at week 24 (post-boosters). Further analysis showed that the change in the EEG based BCI ADHD severity measure correlated with the change ADHD Rating Scale scores. The BCI-based attention training game system is a potential new treatment for ADHD.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01344044","term_id":"NCT01344044"}}NCT01344044     

Predictors of relapse or maintenance of response in pediatric and adult patients with attention-deficit/hyperactivity disorder following discontinuation of long-term treatment with atomoxetine

We identified relapse/maintenance-of-response (MOR) predictors following discontinuation of long-term atomoxetine treatment in pediatric and adult patients with attention-deficit/hyperactivity disorder (ADHD) and assessed correlations between ADHD symptoms and quality of life (QoL). Post hoc analyses of data from two randomized, double-blind, placebo-controlled, phase 3 withdrawal studies in patients with ADHD meeting predefined response criteria before randomization. Study 1: patients (N = 163; 6–15 years) received atomoxetine (1.2–1.8 mg/kg/day) for 1 year, followed by randomization to atomoxetine (n = 81) or placebo (n = 82) for 6 months. Study 2: patients (N = 524; 18–50 years) received atomoxetine (80–100 mg/day) for ~6 months, followed by randomization to atomoxetine (n = 266) or placebo (n = 258) for ~6 months. Placebo patients were used for the analyses. Relapse: ≥50% worsening of prerandomization improvement in ADHD symptoms and ≥2 level severity increase on the Clinical Global Impression-Severity (CGI-S) scale at 2 consecutive visits; MOR: retaining ≥75% of prerandomization symptom improvement and CGI-S ≤ 2 at all visits (study 1); retaining ≥70% of prerandomization symptom improvement and CGI-S ≤ 3 at all visits (study 2). In adults, statistically significantly (P ≤ .05) increased likelihood of relapse was associated with prerandomization presence of Conners’ Adult Attention-Deficit/Hyperactivity Disorder Rating Scale-Investigator-Rated:Screening Version (CAARS-Inv:SV) items “difficulty awaiting turn” and “careless mistakes.” In pediatric patients, less MOR was associated with prerandomization presence of ADHD Rating Scale-IV-Parent Version Investigator-Rated item “does not listen”; in adults, less MOR was associated with prerandomization presence of CAARS-Inv:SV items “loses things” and “difficulty awaiting turn.” Changes in patients’ QoL after withdrawal from atomoxetine moderately correlated with changes in ADHD symptoms in pediatric patients and mildly in adults.     

Self-esteem in adolescent patients with attention-deficit/hyperactivity disorder during open-label atomoxetine treatment: psychometric evaluation of the Rosenberg Self-Esteem Scale and clinical findings

To report on (1) psychometric properties of the Rosenberg Self-Esteem Scale (SES) studied in adolescents with ADHD, (2) correlations of SES with ADHD scale scores, and (3) change in patient-reported self-esteem with atomoxetine treatment. ADHD patients (12–17 years), treated in an open-label study for 24 weeks. Secondary analyses on ADHD symptoms (assessed with ADHD-RS, CGI, GIPD scales) and self-esteem (SES) were performed. One hundred and fifty-nine patients were treated. A dichotomous structure of the SES could be confirmed. Reliability and internal consistency were moderate to excellent. Highest coefficients were found for the correlation between SES and GIPD scores. Self-esteem significantly increased over time, accompanied by an improvement of ADHD symptoms and related perceived difficulties. The Rosenberg SES was shown to be internally consistent, reliable, and sensitive to treatment-related changes of self-esteem. According to these findings, self-esteem may be an important individual patient outcome beyond the core symptoms of ADHD.     

Sensitive quantification of atomoxetine in human plasma by HPLC with fluorescence detection using 4-(4,5-diphenyl-1H-imidazole-2-yl) benzoyl chloride derivatization

The first HPLC-fluorescence method for the determination of atomoxetine in human plasma was developed and validated. Atomoxetine was derivatized with 4-(4,5-diphenyl-1H-imidazol-2-yl) benzoyl chloride (DIB-Cl) under mild conditions, and separated isocratically on a C18 column using a HPLC system with fluorescence detection (lambdaex: 318 nm, lambdaem: 448 nm). A linear calibration curve was obtained over the concentration range 1-1000 ng/mL (r=0.999). The limit of detection (S/N=3) was 0.3 ng/mL. The relative standard deviations of intra-day and inter-day variations were < or =8.30% and 7.47%, respectively. This method is rapid, sensitive, and suitable for both basic and clinical studies of atomoxetine.     

Atomoxetine-Induced Increases in Monoamine Release in the Prefrontal Cortex are Similar in Spontaneously Hypertensive Rats and Wistar-Kyoto Rats

Spontaneously hypertensive rats (SHRs) are used as a model for attention-deficit/hyperactivity disorder (ADHD), since SHRs are hyperactive and show defective sustained attention in behavioral tasks. The psychostimulants amphetamine and methylphenidate and the selective norepinephrine reuptake inhibitor atomoxetine are used as ADHD medications. The effects of high K⁺ stimulation or psychostimulants on brain norepinephrine or dopamine release in SHRs have been previously studied both in vitro and in vivo, but the effects of atomoxetine on these neurotransmitters have not. The present study examined the effects of administration of atomoxetine on extracellular norepinephrine, dopamine, and serotonin levels in the prefrontal cortex of juvenile SHRs and Wistar-Kyoto (WKY) rats. Baseline levels of prefrontal norepinephrine, dopamine, and serotonin were similar in SHRs and WKY rats. Systemic administration of atomoxetine (3 mg/kg) induced similar increases in prefrontal norepinephrine and dopamine, but not serotonin, levels in both strains. Furthermore, there was no difference in high K⁺-induced increases in extracellular norepinephrine, dopamine, and serotonin levels in the prefrontal cortex between SHRs and WKY rats. These findings indicate that monoamine systems in the prefrontal cortex are similar between SHRs and WKY rats.