Manifestation of Adult Attention-Deficit/Hyperactivity Disorder: Atomoxetine
Atomoxetine (Eli Lilly), a selective norepinephrine reuptake inhibitor (SNRI), is indicated for the treatment of ADHD in children and specifically in adults. As one of the only drugs with FDA approval for adult ADHD, atomoxetine has the most evidence available in the literature to support such use.
Two phase 3 trials (n = 280 and n = 256) examined the effects of atomoxetine in reducing adult ADHD symptoms of inattention and hyperactivity/impulsivity using the Conners Adult ADHD Rating Scale (CAARS). Each trial was a 10-week, multicenter, randomized, double-blind, placebo-controlled study. Adults who met DSM-IV criteria for ADHD, as assessed by clinical history and confirmed by the Conners’ Adult ADHD Diagnostic Interview for DSM-IV, were enrolled if they had at least moderate symptom severity. In both studies, atomoxetine reduced ADHD symptoms more than placebo did. Reductions in CAARS-Investigator Rated total ADHD symptoms scores were -9.5 and -10.5 for atomoxetine in the first and second studies and -6.0 (P = .005) and -6.7 (P = .002) for placebo, respectively.
In aggregate, 8.5% of the subjects (or 23/270) receiving discontinued use because of adverse events. The most common reasons for discontinuation included insomnia (n = 3), chest pain (n = 2), palpitations (n = 2), and urinary retention (n = 2).
On September 29, 2005, the FDA requested the addition of a boxed warning to the package insert, stating that short-term studies of atomoxetine showed an increased risk of suicidal ideation in children and adolescents. The risk of suicidal ideation in adults is not yet known.
Of the 526 patients enrolled in the two phase 3 trials, 385 (71.8%) voluntarily chose to enter a three-year, open-label continuation study. The primary outcome measure was the Conners’ Adult ADHD Rating Scale-Investigator Rated: Screening Version (CAARS-Inv: SV) total ADHD symptom score. All patients who chose to participate in the open-label continuation study received atomoxetine. The mean change in CAARS-Inv: SV total ADHD symptom score was -9.7 from a mean baseline score of 29.2, representing a 35.2% reduction (P < .001).
Fifty-eight subjects withdrew from the trial because of a lack of efficacy. Baseline demographic characteristics between the two treatment groups did not differ, but baseline symptom scores did, perhaps because patients who opted for the continuation study were those who responded best in the previous studies. The discontinuation rate attributable to adverse events during the open-label trial was 10.9%, compared with 8.5% during the acute studies.
A number of other drugs have been used in the treatment of adult ADHD with some degree of success. Tricyclic anti-depressants, such as desipramine (Norpramin, Sanofi-Aventis), have been studied, as have (Wellbutrin canadian, Wellbutrin Sustained Release (SR) and Extended Release (XL), Zyban, GlaxoSmithKline) and modafinil.
In one of the first studies examining the efficacy of bupro-pion in the treatment of adult ADHD, Wender and Reimherr treated 19 subjects with the dopamine reuptake inhibitor in an open-label fashion. These subjects had been previously treated with either stimulants or monoamine oxidase (MAO) inhibitors. Fourteen of the 19 subjects experienced moderate-to-marked benefit from bupropion, and 10 of those chose to continue rather than their previous medication.
More recently, Wilens et al. conducted a six-week, double-blind, placebo-controlled, randomized trial in 40 adults; 21 received sustained-release bupropion, and 19 received placebo. In this study, bupropion was associated with a greater reduction in ADHD symptoms (42%) than placebo (24%) (P = .05), according to scores on the CGI scale.
The Wilens team also performed a six-week open trial of bupropion in 36 adults with ADHD plus bipolar disorder. Although the study was not placebo-controlled, patients demonstrated significant reductions on the ADHD symptom checklist (-55°%; P < .001) and on the CGI scale (-40°%; P < .001), that were consistent with previous findings.
In one of the few comparative studies of medications to treat ADHD in adults, Kuperman et al. examined the effects of sustained-release bupropion, methylphenidate, and placebo. The primary outcome measure of the randomized, double-blind, parallel trial was the response rate, based on improvements in CGI scores. Methylphenidate, and placebo resulted in improvements of 64%, 50%, and 27%, respectively; however, the differences in response rates between the medications and placebo were not statistically significant (P = 0.14).
Although the study was small, with only 30 patients, it was powered to detect a significant treatment effect. However, the placebo response rate was considerably higher than expected.