Elsevier

Biological Psychiatry

Volume 53, Issue 2, 15 January 2003, Pages 112-120
Biological Psychiatry

Original article
Atomoxetine in adults with ADHD: two randomized, placebo-controlled studies

https://doi.org/10.1016/S0006-3223(02)01671-2Get rights and content

Abstract

Background

Attention-deficit/hyperactivity disorder (ADHD) has been less studied in adults than in children, and the treatment studies reported to date have been small, single-center trials. To assess the efficacy of atomoxetine, a new and highly selective inhibitor of the norepinephrine transporter, we conducted two large, multicenter treatment trials.

Methods

Two identical studies using randomized, double-blind, placebo-controlled designs and a 10-week treatment period were conducted in adults with DSM-IV-defined ADHD as assessed by clinical history and confirmed by a structured interview (study I, n = 280; study II, n = 256). The primary outcome measure was a comparison of atomoxetine and placebo using repeated measures mixed model analysis of postbaseline values of the Conners’ Adult ADHD Rating Scale.

Results

In each study, atomoxetine was statistically superior to placebo in reducing both inattentive and hyperactive and impulsive symptoms as assessed by primary and secondary measures. Discontinuations for adverse events among atomoxetine patients were under 10% in both studies.

Conclusions

Atomoxetine appears to be an efficacious treatment for adult ADHD. Its lack of abuse potential may be an advantage for many patients.

Introduction

Attention-deficit/hyperactivity disorder (ADHD) is a psychiatric disorder characterized by difficulties sustaining attention and difficulties with impulse control. Evidence suggests that genetic factors are important in its pathogenesis (Hudziak 1997) and that its pathophysiology involves alterations in central dopaminergic and noradrenergic tone Biederman and Spencer 1999a, Safer 2000. The disorder begins early in life and has been studied primarily in children, among whom its prevalence is 3–7% (American Psychiatric Association 2000). As children mature, symptoms can become less problematic, most likely through developmental changes in the brain, by learning to compensate for deficits with adaptive behaviors, or by gravitating toward environments that make fewer demands in areas of impairment; however, the disorder often persists into adulthood Biederman et al 2000, Weiss 1985 and is associated with significant morbidity and undesirable outcomes Brown and Borden 1986, Hechtman 1996, Klein and Mannuzza 1989, Klein and Mannuzza 1991, Murphy and Barkley 1996, Seidman et al 1998, Thorley 1984, Weiss 1996, Weiss and Hechtman 1993.

Pharmacotherapies effective in children appear to be valuable in adults Spencer et al 1995, Wender and Reimherr 1990, Wender and Reimherr 1990, Wilens et al 1996; however, the literature on treatment of adult ADHD is limited. Published studies have been small and have differed in the methodologies used for diagnostic ascertainment and symptom assessment. No large, parallel-design, placebo-controlled trial using rigorous diagnostic and assessment procedures has been reported to date for any agent.

The most widely used medications for ADHD are the psychostimulants methylphenidate and amphetamine (Popper 2000). There is, however, considerable interest in alternative, nonstimulant therapies, because some patients respond poorly to stimulants or are unable to tolerate them. In addition, some physicians are reluctant to use stimulants because of concerns about misuse in a population at increased risk for substance abuse (Wilens and Biederman 1992), although whether treatment with psychostimulants increases risk for substance abuse in adult ADHD is controversial Biederman et al 1999b, Wilens 2000. The current alternatives to stimulants are primarily the antidepressants desipramine and bupropion. These are efficacious in children Biederman et al 1989, Conners et al 1996 and have been superior to placebo in small studies in adults Wilens et al 1996, Wilens et al 2001, but neither drug is approved for the treatment of ADHD, and desipramine has a low therapeutic index and can adversely affect cardiac conduction.

The investigational drug atomoxetine is a potent inhibitor of the presynaptic norepinephrine transporter (Ki∼4.5nM) with minimal affinity for other noradrenergic receptors or for other neurotransmitter transporters. It is efficacious in children and adolescents with ADHD (Michelson et al 2001), and preliminary data suggest efficacy in adults (Spencer et al 1998). Atomoxetine does not appear to have abuse potential (Heil et al 2002), and unlike desipramine, atomoxetine is not associated with adverse effects on cardiac conduction (Michelson et al 2001). To assess the efficacy of atomoxetine for adult ADHD, we conducted two large, prospective, double-blind, placebo-controlled, randomized studies. We report the results of these studies here.

Section snippets

Methods and materials

Two identical randomized, double-blind, placebo-controlled studies were conducted concurrently at 17 (study I) and 14 (study II) outpatient sites in North America. Adults who met DSM-IV (American Psychiatric Association 2000) criteria for ADHD as assessed by clinical interview and confirmed by the Conners’ Adult ADHD Diagnostic Interview for DSM-IV (CAAR-D; Conners et al 1999) were recruited from clinics and by advertisement. Patients were required to have at least moderate symptom severity,

Results

Of 448 patients initially assessed in study I, 280 met entry criteria and were randomized to atomoxetine (n = 141) or placebo (n = 139). In study II, 388 patients were assessed, and 256 met entry criteria and were randomized to atomoxetine (n = 129) or placebo (n = 127). Details of reasons for failure to be randomized (including all patients who signed consent but discontinued before the placebo lead-in as well as those who entered the placebo lead-in) are provided in Figure 1, Figure 2. Among

Discussion

In two large, identical studies conducted concurrently, atomoxetine was superior to placebo in reduction of ADHD symptoms in adults. Outcomes were similar for most measures across the two studies, and both attention and hyperactive/impulsive symptoms improved with drug treatment.

Psychostimulants (methylphenidate and amphetamine), desipramine, and bupropion have been reported to be effective in adults with ADHD (Wilens et al 2001); however, all studies reported to date have been small, several

Acknowledgements

This research was funded by Eli Lilly and Company. The authors thank Nancy J. Trapp for her contributions to this manuscript. The following were study investigators for these studies: Lenard Adler, M.D., Hospital for Joint Disease, New York, NY; Richard J Burch, M.D., University of Missouri—Columbia, Columbia, MO; Edward Cherlin, M.D., Valley Clinical Research, El Centro, CA; Anthony P. Dietrich, M.D., Neuropsychiatric Associates, Woodstock, VT; David Feifel, M.D., Ph.D., UCSD Medical

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    Atomoxetine was originally called tomoxetine. The name was changed to avoid confusion with tamoxifen which might lead to errors in dispensing drug.

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