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.

Atomoxetine treatment in adults with attention-deficit/hyperactivity disorder and comorbid social anxiety disorder.

BACKGROUND: To evaluate the effect of atomoxetine (ATX) on attention-deficit/hyperactivity disorder (ADHD) and comorbid social anxiety disorder in adults. METHODS: Randomized, double-blind, placebo-controlled, conducted in adults with ADHD and social anxiety disorder. Patients received 40-100 mg ATX (n=224) or placebo (n=218) for 14 weeks following a 2-week placebo lead-in period. Efficacy measures included the Conners' Adult ADHD Rating Scale: Investigator-Rated: Screening Version (CAARS:Inv:SV), Liebowitz Social Anxiety Scale (LSAS), Clinical Global Impression-Overall-Severity (CGI-O-S), State-Trait Anxiety Inventory (STAI), Social Adjustment Scale-Self Report (SAS), and Adult ADHD Quality of Life Scale-29 (AAQoL). Safety and tolerability were also assessed. RESULTS: ATX mean change (-8.7+/-10.0) from baseline (29.6+/-10.4) on CAARS:Inv:SV Total ADHD Symptoms score was significantly greater than placebo mean change (-5.6+/-10.2) from baseline (31.2+/-9.4; P<.001). ATX mean change (-22.9+/-25.3) from baseline (85.3+/-23.6) on LSAS Total score was significant compared to placebo mean change (-14.4+/-20.3) from baseline (82.1+/-21.3; P<.001). The visit-wise analysis revealed greater improvement on the CAARS:Inv:SV Total ADHD Symptoms score and LSAS Total score for ATX at every time point throughout the study (P values

A 7-week, randomized, double-blind trial of olanzapine/fluoxetine combination versus lamotrigine in the treatment of bipolar I depression.

OBJECTIVE: Determine the efficacy and tolerability of olanzapine/fluoxetine combination (OFC) for treatment of acute bipolar I depression compared with lamotrigine. METHOD: The 7-week, acute phase of a randomized, double-blind study compared OFC (6/25, 6/50, 12/25, or 12/50 mg/day; N = 205) with lamotrigine ([LMG] titrated to 200 mg/day; N = 205) in patients with DSM-IV-diagnosed bipolar I disorder, depressed. The study was conducted from November 2003 to August 2004. RESULTS: Completion rates were similar between treatments (OFC, 66.8% vs. LMG, 65.4%; p = .835). OFC-treated patients had significantly greater improvement than lamotrigine-treated patients in change from baseline across the 7-week treatment period on the Clinical Global Impressions-Severity of Illness scale (primary outcome) (p = .002, effect size = 0.26), Montgomery-Asberg Depression Rating Scale (MADRS) (p = .002, effect size = 0.24), and Young Mania Rating Scale total scores (p = .001, effect size = 0.24). Response rates did not significantly differ between groups when defined as > or = 50% reduction in MADRS score (OFC, 68.8% vs. LMG, 59.7%; p = .073). Time to response was significantly shorter for OFC-treated patients (median days [95% CI] = OFC, 17 [14 to 22] vs. LMG, 23 [21 to 34]; p = .010). There was a significant difference in incidence of "suicidal and self-injurious behavior" adverse events (OFC, 0.5% vs. LMG, 3.4%; p = .037). Somnolence, increased appetite, dry mouth, sedation, weight gain, and tremor occurred more frequently (p < .05) in OFC-treated patients than lamotrigine-treated patients. Weight, total cholesterol, and triglyceride levels were significantly elevated in OFC-treated patients compared with lamotrigine-treated patients (all p < or = .001). CONCLUSIONS: Patients with acute bipolar I depression had statistically significantly greater improvement in depressive and manic symptoms, more treatment-emergent adverse events, greater weight gain, and some elevated metabolic factors with OFC than lamotrigine. Treatment differences were of modest size.

Development of renal function tests for measurement of urine concentrating ability, urine acidification, and glomerular filtration rate in female cynomolgus monkeys.

This study was conducted to develop tests for evaluation of uri ne concentratingability, urine acidification ability, an dglomerular filtration rate in cynomolgus macaques. In female cynomolgus macaques, baseline urine specific gravity ranged from 1.005 to 1.031, and urine osmolality ranged from 182 to 1081 mOsm/kg. A dose of 0.4 microg/kg desmopressin acetate resulted in a urine specific gravity that ranged from 1.019 to 1.043 and an osmolality that ranged from 432 to 1298 mOsm/kg. Desmopressin acetate administration increased urine specific gravity and osmolality in each animal evaluated. Baseline urine pH in these animals ranged from 6.4 to 8.2. A dose of orally administered ammonium chloride (0.1 g/kg) resulted in a urine pH that ranges from 4.1 to 7.1. Ammonium chloride administration decreased urine pH in each animal tested. Evaluation of glomerular filtration rate was accomplished through urine collection and timed blood and urine samples after oral hydration with 0.45% sodium chloride. Blood samples were analyzed for creatinine, osmolality, sodium, potassium, and chloride. Urine samples were analyzed for volume, creatinine, osmolality, sodium, potassium, and chloride. Creatinine clearance, osmolality clearance, and electrolyte fractional clearance were calculated from the values. Osmolality clearance ranged from 0.03 to 0.07 ml/kg/min, creatinine clearance ranged from 1.84 to 2.53 ml/kg/min, fractional excretion of sodium ranged from 0.17% to 0.77%, fractional excretion of potassium ranged from 4.46% to 19.87%, and fractional excretion of chloride ranged from 0.25% to 1.08%. The response to desmopressin acetate and ammonium chloride and the osmolality, creatinine concentration, and fractional electrolyte excretion were consistent in individual animals with repeat testing. No adverse events were associated with the tests. The results of these tests are consistent with repeat testing in individual animals. These tests likely can be used for clinical assessment of renal function in cynomolgus macaques or for collection of experimental data.

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.