Atomoxetine treatment of attention-deficit/hyperactivity disorder in young adults with assessment of functional outcomes: a randomized, double-blind, placebo-controlled clinical trial.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is associated with significant impairment in multiple functional domains. This trial evaluated efficacy in ADHD symptoms and functional outcomes in young adults treated with atomoxetine. METHODS: Young adults (18-30 years old) with ADHD were randomized to 12 weeks of double-blind treatment with atomoxetine (n = 220) or placebo (n = 225). The primary efficacy measure of ADHD symptom change was Conners' Adult ADHD Rating Scale (CAARS): Investigator-Rated: Screening Version Total ADHD Symptoms score with adult prompts. Secondary outcomes scales included the Adult ADHD Quality of Life-29, Clinical Global Impression-ADHD-Severity, Patient Global Impression-Improvement, CAARS Self-Report, Behavior Rating Inventory of Executive Function-Adult Version Self-Report, and assessments of depression, anxiety, sleepiness, driving behaviors, social adaptation, and substance use. RESULTS: Atomoxetine was superior to placebo on CAARS: Investigator-Rated: Screening Version (atomoxetine [least-squares mean ± SE, -13.6 ± 0.8] vs placebo [-9.3 ± 0.8], 95% confidence interval [-6.35 to -2.37], P < 0.001), Clinical Global Impression-ADHD-Severity (atomoxetine [-1.1 ± 0.1] vs placebo [-0.7 ± 0.1], 95% confidence interval [-0.63 to -0.24], P < 0.001), and CAARS Self-Report (atomoxetine [-11.9 ± 0.8] vs placebo [-7.8 ± 0.7], 95% confidence interval [-5.94 to -2.15], P < 0.001) but not on Patient Global Impression-Improvement. In addition, atomoxetine was superior to placebo on Adult ADHD Quality of Life-29 and Behavior Rating Inventory of Executive Function-Adult Version Self-Report. Additional assessments failed to detect significant differences (P ≥ 0.05) between atomoxetine and placebo. The adverse event profile was similar to that observed in other atomoxetine studies. Nausea, decreased appetite, insomnia, dry mouth, irritability, dizziness, and dyspepsia were reported significantly more often with atomoxetine than with placebo. CONCLUSIONS: Atomoxetine reduced ADHD symptoms and improved quality of life and executive functioning deficits in young adults compared with placebo. Atomoxetine was also generally well tolerated.

Stimulant formulation and motivation for nonmedical use of prescription attention-deficit/hyperactivity disorder medications in a college-aged population.

There is relatively little research examining motives for nonmedical use (NMU) of attention-deficit/hyperactivity disorder (ADHD) medications and predictors of motivation. We present results of a secondary analysis of an Internet-based epidemiological survey to explore the relationship between stimulant formulation and motivation for NMU of ADHD stimulant medications in a college-aged population. Demographic predictors of motivation to engage in NMU were also explored to investigate the potential correlates of recreational versus performance-enhancement motivations. Respondents scoring higher on the Adult ADHD Self-Report Scale were significantly more likely to engage in NMU of ADHD stimulant medications. Those using extended release (ER) stimulant formulations were less likely to endorse "staying awake" as a reason for NMU compared to those using immediate release (IR) stimulant formulations.

Effects of open-label atomoxetine on African-American and Caucasian pediatric outpatients with attention-deficit/hyperactivity disorder.

BACKGROUND: Data on the management of attention-deficit/hyperactivity disorder (ADHD) in African-American children and adolescents are limited. METHODS: This study sought to evaluate the tolerability, safety, and efficacy of atomoxetine hydrochloride in the management of ADHD in African-American children and adolescents by conducting a post hoc subgroup analysis of 2 multicenter, open-label studies. RESULTS: Atomoxetine was safe and well tolerated, with >or=3.0% of African-Americans and Caucasians discontinuing treatment because of adverse events. A significantly higher proportion of Caucasians reported >or=1 treatment-emergent adverse event, including vomiting (7.2% vs 1.2%; P=.037) and fatigue (6.1% vs 0%; P=.012). No serious safety concerns were observed. Changes from baseline in height, weight, and hemodynamic variables were modest and similar in both racial subgroups. African-Americans and Caucasians showed significant improvement from baseline to end point in the mean ADHD Rating Scale-IV-Parent Version: Investigator Administered and Scored (ADHDRS-IV-P:I). Scores decreased by 20.1 in African-Americans and by 19.55 in Caucasians, without significant between-group differences. Patients in both racial groups experienced similar, significant improvements in ADHDRS-IV-P:I inattention and hyperactivity-impulsivity symptoms, Clinical Global Impression-ADHD-Severity, and Conners' Parent Rating Scale-Revised: Short Form. CONCLUSIONS: Atomoxetine exhibited similar tolerability, safety, and efficacy profiles in African-Americans and Caucasians with ADHD.

Latino versus Caucasian response to atomoxetine in attention-deficit/hyperactivity disorder.

ABSTRACT We examined the effects of atomoxetine in Latino (n = 108) versus Caucasian (n = 1090) pediatric outpatients (aged 6 to <18 years) during the first 10-11 weeks of treatment in two multicenter, open-label trials. Mean modal doses were not significantly different in Latinos (1.22 mg/kg per day) versus Caucasians (1.27 mg/kg per day; p = 0.22). Both groups showed significant and similar improvements: Mean ADHD Rating Scale-IV-Parent Version: Investigator Administered and Scored (ADHDRS-IV-P:I) scores decreased by 54% in Latinos (40.9-18.9; p < 0.001) and by 52% in Caucasians (37.7-18.2; p < 0.001). Other efficacy measures, such as Conners' Parent Rating Scale-Revised: Short Form (CPRS-R:S) and Clinical Global Impressions-ADHD-Severity (CGI-ADHD-S), demonstrated similar and significant decreases. The only significant between-group difference was a greater decrease in the ADHDRS-IV-P:I Hyperactive/Impulsive subscale at weeks 8-11 for Latinos; however, Latinos had higher baseline scores compared with Caucasians. This was not demonstrated in the CPRS-R:S Hyperactivity subscale. There was a significantly higher frequency of CYP2D6 slow metabolizers in Caucasians compared with Latinos. Caucasians reported significantly more abdominal and throat pain, whereas Latinos reported more decreased appetite and dizziness, but no differences in other common adverse events were reported. No suicidal behavior was reported in either group. We found that Latino and Caucasian children with attention-deficit/hyperactivity disorder (ADHD) exhibit a similar pattern of efficacy and tolerability with atomoxetine. The lack of placebo controls was a limitation of this study.

Discriminative-stimulus, self-reported, performance, and cardiovascular effects of atomoxetine in methylphenidate-trained humans.

Atomoxetine is marketed as a nonstimulant medication indicated for the treatment of attention-deficit/hyperactivity disorder in adults. Previous laboratory research suggests that atomoxetine has limited abuse potential but that some of its behavioral effects might overlap with traditional psychomotor stimulants like methylphenidate and d-amphetamine. A drug with this profile might be useful for the treatment of stimulant dependence. The aim of this experiment was to compare the discriminative-stimulus and self-reported effects of atomoxetine with methylphenidate, damphetamine, and triazolam in humans who had acquired a methylphenidate (30 mg) discrimination. Six healthy subjects with a recent history of nontherapeutic stimulant use were enrolled in this outpatient study. After subjects acquired the methylphenidate discrimination, a range of doses of methylphenidate (5-30 mg), atomoxetine (15-90 mg), d-amphetamine (2.5-15 mg), triazolam (0.06-0.375 mg), and placebo were tested. To more fully characterize the behavioral effects of atomoxetine, a battery of self-reported drug-effect questionnaires, a performance task, and cardiovascular assessments were also included. Methylphenidate and d-amphetamine increased drug-appropriate responding and produced typical stimulant-like effects (e.g., increased ratings of "Active, Alert, Energetic"). Atomoxetine partially substituted for methylphenidate (i.e., 33%-50%) and produced some dose-dependent, stimulant-like, subject-rated drug effects, although the magnitude of these effects was less than d-amphetamine and methylphenidate and generally did not attain statistical significance. These data suggest that the behavioral effects of atomoxetine overlap to a small degree with psychomotor stimulants and that it has low abuse potential.

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 NCT00510276.

Neurophysiologic predictors of response to atomoxetine in young adults with attention deficit hyperactivity disorder: a pilot project.

Atomoxetine is a non-stimulant medication with sustained benefit throughout the day, and is a useful pharmacologic treatment option for young adults with Attention-Deficit/Hyperactivity Disorder (ADHD). It is difficult to determine, however, those patients for whom atomoxetine will be both effective and advantageous. Patients may need to take the medication for several weeks before therapeutic benefit is apparent, so a biomarker that could predict atomoxetine effectiveness early in the course of treatment could be clinically useful. There has been increased interest in the study of thalamocortical oscillatory activity using quantitative electroencephalography (qEEG) as a biomarker in ADHD. In this study, we investigated qEEG absolute power, relative power, and cordance, which have been shown to predict response to reuptake inhibitor antidepressants in Major Depressive Disorder (MDD), as potential predictors of response to atomoxetine. Forty-four young adults with ADHD (ages 18-30) enrolled in a multi-site, double-blind placebo-controlled study of the effectiveness of atomoxetine and underwent serial qEEG recordings at pretreatment baseline and one week after the start of medication. qEEG measures were calculated from a subset of the sample (N = 29) that provided useable qEEG recordings. Left temporoparietal cordance in the theta frequency band after one week of treatment was associated with ADHD symptom improvement and quality of life measured at 12 weeks in atomoxetine-treated subjects, but not in those treated with placebo. Neither absolute nor relative power measures selectively predicted improvement in medication-treated subjects. Measuring theta cordance after one week of treatment could be useful in predicting atomoxetine treatment response in adult ADHD.

A review of the abuse potential assessment of atomoxetine: a nonstimulant medication for attention-deficit/hyperactivity disorder.

RATIONALE: Treatment of attention-deficit/hyperactivity disorder (ADHD) has for many years relied on psychostimulants, particularly various formulations of amphetamines and methylphenidate. These are central nervous system stimulants and are scheduled because of their abuse potential. Atomoxetine (atomoxetine hydrochloride; Strattera®) was approved in 2002 for treatment of ADHD, and was the first nonstimulant medication approved for this disorder. It was classified as an unscheduled medication indicating a low potential for abuse. However, the abuse potential of atomoxetine has not been reviewed. OBJECTIVES: In this article, we review the evidence regarding abuse potential of atomoxetine, a selective inhibitor of the presynaptic norepinephrine transporter, which is unscheduled/unrestricted in all countries where it is approved. METHODS: Results from receptor binding, in vitro electrophysiology, in vivo microdialysis, preclinical behavioral, and human laboratory studies have been reviewed. RESULTS: Atomoxetine has no appreciable affinity for, or action at, central receptors through which drugs of abuse typically act, i.e., dopamine transporters, GABA(A) receptors, and opioid µ receptors. In behavioral experiments in rodents, atomoxetine does not increase locomotor activity, and in drug discrimination studies, its profile is similar to that of drugs without abuse potential. Atomoxetine does not serve as a reinforcer in monkey self-administration studies, and human laboratory studies suggest that atomoxetine does not induce subjective effects indicative of abuse. CONCLUSION: Neurochemical, preclinical, and early clinical studies predicted and supported a lack of abuse potential of atomoxetine, which is consistent with the clinical trial and postmarketing spontaneous event data in the past 10 years.

Atomoxetine treatment outcomes in adolescents and young adults with attention-deficit/hyperactivity disorder: results from a post hoc, pooled analysis.

BACKGROUND: Many children with attention-deficit/hyperactivity disorder (ADHD) continue to experience this disorder as adults, which may, in part, be due to the discontinuity of health care that often occurs during the transition period between late adolescence and young adulthood. Although atomoxetine is reported to be efficacious in both adolescents and young adults, no longitudinal studies have been designed to assess directly the effects of atomoxetine treatment during this transition period. As a first step, we present the results of a post hoc, pooled analysis that compared the efficacy and safety profile of atomoxetine in these 2 patient populations. OBJECTIVE: The aim of the present study was to assess the efficacy and safety profile of atomoxetine treatment in adolescents and young adults with ADHD. METHODS: A post hoc, pooled analysis was conducted by combining data from 6 double-blind trials (6-9 weeks in duration) that studied adolescents (12-17 years of age; atomoxetine, n = 154; placebo, n = 88; mean final dose = 1.38 mg/kg) and 3 trials (10 weeks in duration) that studied young adults (18-30 years of age; atomoxetine, n = 117; placebo, n = 125; mean final dose = 1.21 mg/kg). Efficacy measures used in these analyses were ADHD Rating Scale (ADHDRS) for adolescents, Conners' Adult ADHD Rating Scale (CAARS) for young adults, and Clinical Global Impressions-ADHD-Severity (CGI-ADHD-S) for both age groups. Treatment response was defined as ≥30% reduction from baseline in total ADHD symptom score. RESULTS: In adolescents (mean age, 13.4 years), atomoxetine improved ADHD significantly compared with placebo (ADHDRS total score change, -12.9 vs -7.5; P < 0.001). In young adults (mean age, 24.7 years), atomoxetine improved ADHD significantly (CAARS total score change, -13.6 vs -7.7; P < 0.001; CGI-ADHD-S change, -1.1 vs -0.6; P < 0.001). No significant treatment-by-age subgroup interaction was observed. Tolerability was similar for both age subgroups, except for treatment-emergent nausea, which occurred significantly more frequently with atomoxetine than with placebo in young adults (13.7% vs 4.8%, respectively; P = 0.024); in adolescents no statistically significant differences were observed in frequency of nausea between atomoxetine and placebo treatment (4.5% vs 10.2%, respectively; P = 0.108). CONCLUSIONS: Results from this post hoc, pooled analysis suggest that acute treatment with atomoxetine was efficacious in both adolescent and young adult patients with ADHD. The safety profile findings from this study were consistent with the previously reported atomoxetine safety and tolerability profiles, suggesting that it may be continued during the transition from adolescence to young adulthood.

Relationship between African-American or Caucasian origin and outcomes in the olanzapine treatment of acute mania: a pooled analysis of three adult studies conducted in the United States of America.

The aim of this study was to explore the role of ethnic origin in the treatment of acute bipolar mania. Treatment outcomes were studied in a post-hoc analysis of African-American (AA, n=41) and Caucasian (CA, n=190) adults treated with olanzapine in three studies conducted in the United States of America. Baseline demographics were similar except that the AA cohort had fewer women compared with the CA cohort (37 vs. 58%; P=0.01). Daily mean modal olanzapine dose and study discontinuation rate for AA and CA were: 16.2 mg vs. 16.6 mg and 41.5 vs. 25.3% (P=0.03), respectively. There were four (23.5% of discontinuers) and 19 (39.6% of discontinuers, P=0.14) discontinuations because of a poor response in the AA and CA groups, respectively. Drug exposure for the AA cohort was 18.7 days and that of the CA cohort was 19.3 days. Both cohorts showed similar symptom improvements, and safety outcomes were not statistically significantly different except for the following treatment-emergent adverse event frequencies for AA and CA cohorts, respectively: agitation (24.4 vs. 10.5%, P=0.04); dysmenorrhoea (20.0 vs. 3.6%, P=0.04); and dizziness postural (7.3 vs. 1.1%, P=0.04). Although study findings [limited by a smaller (18% of total population) AA cohort] need replication, they suggest that while many outcomes were similar in both cohorts, clinicians could benefit from the awareness of factors in the AA population that possibly influence study discontinuation rates, treatment-emergent adverse event reporting, and participation by sex.

Olanzapine/fluoxetine combination in patients with treatment-resistant depression: rapid onset of therapeutic response and its predictive value for subsequent overall response in a pooled analysis of 5 studies.

OBJECTIVE: To characterize response profiles of olanzapine/fluoxetine combination therapy in treatment-resistant depression (TRD) and to investigate predictive relationships of early improvement with olanzapine/fluoxetine combination for subsequent response/remission during the acute phase of treatment. METHOD: Results were pooled from 5 outpatient studies comparing oral olanzapine/fluoxetine combination, fluoxetine, or olanzapine for a maximum of 8 weeks in patients with TRD who had at least 1 historical antidepressant treatment failure during the current episode and who failed a prospective antidepressant therapy during the study lead-in period. Mean Montgomery-Asberg Depression Rating Scale (MADRS) total and core mood items scores from the 8-week evaluation period were compared across treatment groups. Positive and negative predictive values (PPVs, NPVs) were computed from olanzapine/fluoxetine combination-treated patients demonstrating response and remission based on whether they demonstrated early improvement. RESULTS: Mean olanzapine/fluoxetine combination MADRS score reductions were significantly greater than fluoxetine by week 0.5 and olanzapine by week 1. Significantly more olanzapine/fluoxetine combination patients demonstrated MADRS onset of response compared with fluoxetine and olanzapine patients (P < .001 for both MADRS total and core mood items). In olanzapine/fluoxetine combination patients, 38.1% exhibited MADRS total score response versus 26.9% of fluoxetine patients (P < .001) and 22.2% of olanzapine patients (P < .001). NPVs for MADRS total and core mood items response and remission ranged from 85.7% to 92.1%; PPVs ranged from 29.9% to 45.1%. CONCLUSIONS: Olanzapine/fluoxetine combination is superior to fluoxetine and olanzapine in producing early improvement in patients with TRD. The absence of early improvement is highly predictive for overall response failure. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00035321.

Prevalence of nonmedical methamphetamine use in the United States.

BACKGROUND: Illicit methamphetamine use continues to be a public health concern in the United States. The goal of the current study was to use a relatively inexpensive methodology to examine the prevalence and demographic correlates of nonmedical methamphetamine use in the United States. METHODS: The sample was obtained through an internet survey of noninstitutionalized adults (n = 4,297) aged 18 to 49 in the United States in 2005. Propensity weighting methods using information from the U.S. Census and the 2003 National Survey on Drug Use and Health (NSDUH) were used to estimate national-level prevalence rates. RESULTS: The overall prevalence of current nonmedical methamphetamine use was estimated to be 0.27%. Lifetime use was estimated to be 8.6%. Current use rates for men (0.32%) and women (0.23%) did not differ, although men had a higher 3-year prevalence rate (3.1%) than women (1.1%). Within the age subgroup with the highest overall methamphetamine use (18 to 25 year olds), non-students had substantially higher methamphetamine use (0.85% current; 2.4% past year) than students (0.23% current; 0.79% past year). Methamphetamine use was not constrained to those with publicly funded health care insurance. CONCLUSION: Through the use of an internet panel weighted to reflect U.S. population norms, the estimated lifetime prevalence of methamphetamine use among 18 to 49 year olds was 8.6%. These findings give rates of use comparable to those reported in the 2005 NSDUH. Internet surveys are a relatively inexpensive way to provide complimentary data to telephone or in-person interviews.