Atomoxetine, a Novel Treatment for Attention-Deficit-Hyperactivity Disorder
September 29, 2004
Alisa K. Christman, Pharm.D.; Joli D. Fermo, Pharm.D.; John S. Markowitz, Pharm.D.
Atomoxetine is the first nonstimulant drug approved by the United States Food and Drug Administration (FDA) for the treatment of attention-deficit-hyperactivity disorder (ADHD), and the only agent approved by the FDA for the treatment of ADHD in adults. Atomoxetine is a norepinephrine transport inhibitor that acts almost exclusively on the noradrenergic pathway. Its mechanism of action in the control and maintenance of ADHD symptoms is thought to be through the highly specific presynaptic inhibition of norepinephrine. Clinical trials to evaluate the short-term effects of atomoxetine in children and adults have shown that atomoxetine is effective in maintaining control of ADHD. Likewise, long-term trials have determined that atomoxetine is effective in preventing relapse of ADHD symptoms without an increase in adverse effects. A comparative trial of atomoxetine with methylphenidate in school-aged children indicated similar safety and efficacy without the abuse liability associated with some psychostimulants. The most commonly reported adverse effects in children and adolescents are dyspepsia, nausea, vomiting, decreased appetite, and weight loss. The rates of adverse events in the trials were similar for both the once- and twice-daily dosing regimens. The discontinuation rate was 3.5% in patients treated with atomoxetine versus 1.4% for placebo and appeared to be dose dependent, with a higher percentage of discontinuation at dosages greater than 1.5 mg/kg/day. In clinical trials involving adults, the emergence of clinically significant or intolerable adverse events was low. The most common adverse events in adults were dry mouth, insomnia, nausea, decreased appetite, constipation, urinary retention or difficulties with micturition, erectile disturbance, dysmenorrhea, dizziness, and decreased libido. Sexual dysfunction occurred in approximately 2% of patients treated with atomoxetine. Atomoxetine should be used with caution in patients who have hypertension or any significant cardiovascular disorder. Overall, atomoxetine therapy in patients with ADHD appears to be effective in controlling symptoms and maintaining remission, with the advantages being comparable efficacy with that of methylphenidate, a favorable safety profile, and non-controlled substance status. Additional long-term studies are needed to determine its continued efficacy for those who require lifelong treatment, and comparative trials against other stimulant and nonstimulant agents.
Attention-deficit-hyperactivity disorder (ADHD) is the most frequently diagnosed neurobehavioral childhood disorder. Although estimates vary, in the United States ADHD occurs at estimated rates of 3-7% in school-aged children and 6% in adults. The number of cases continues to grow each year, and the disorder was identified as a serious public health problem by the Centers for Disease Control and Prevention in 1999. Children often exhibit symptoms of aggressiveness, inattention, hyperactivity, inability to concentrate at school, and difficulty in the completion of simple tasks. The main impairments caused by ADHD are through academic and social dysfunction. Developmental problems such as in reading, spelling, and arithmetic are common as well. Children with ADHD often have trouble communicating appropriately, and 10-54% have speech problems as a result. These impairments may lead to demoralization and poor self-esteem in children, thus causing increased rates of high-risk injuries, tobacco addiction, and substance abuse. Typically, ADHD is diagnosed in boys more often than in girls, possibly because of the observations that boys exhibit much more aggressive behavior and symptoms than do girls.
Childhood ADHD was once believed to be a disorder that would dissipate once the child entered into early adulthood. However, follow-up studies reveal that 10-60% of children with ADHD continue to have symptoms as they become adults. Adults with persistent symptoms of ADHD may experience occupational and vocational dysfunction, continued social impairment, and increased rates of motor-vehicle accidents. Controversy continues to surround the diagnosis and classification of ADHD in adults. Scientifically, the diagnosis is based on the criteria for ADHD as set by the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR). However, as the symptoms of ADHD manifest less frequently with age, some researchers may argue that the criteria for diagnosis of ADHD listed in the DSM-IV-TR are too stringent for adults, since adults must exhibit symptoms in at least two settings. Typically, adults with ADHD exhibit their symptoms strongest in the workplace, whereas symptoms experienced at home may be less recognizable. Adults who express difficulty organizing their finances, completing household chores, or keeping appointments on time may dismiss these behaviors as a personality trait rather than relating them to similar behaviors exhibited at work and associating their condition with ADHD.
Although the intensity and severity of symptoms will decline over time, adults with ADHD find dealing with everyday situations challenging and complex. Time management and work execution become very complicated tasks, whereas they may be observed as simple functions to the adult without ADHD. An issue that continues to further complicate the recognition of ADHD is that no single cause has been identified. Various hypotheses have been presented and are used as a basis to define treatment, such as prenatal and perinatal risk factors, genetics, and neurobiologic deficits that include decreased frontal cortical activity and decreased extracellular dopamine activity.
Traditionally, the pharmacologic treatments of choice for ADHD have been psychostimulant agents such as methylphenidate or dextroamphetamine. Most research suggests that stimulants work to alleviate the symptoms of ADHD through the potentiation of dopamine and, to a lesser extent, norepinephrine in the central nervous system. However, approximately 30% of children and adults with ADHD either do not respond to or do not tolerate psychostimulants. Although the existing psychostimulants have established efficacy, safety, and a generally favorable adverse-effect profile, the existence of patients who do not respond and the prospect of long-term pharmacotherapy, as well as the potential for drug abuse or diversion, have gener-ated support for the development and use of nonstimulant agents for the treatment of ADHD.
Research has shown that the noradrenergic neurotransmitter system is involved with visual attention, sustainment of attention for long periods of time, initiation of an adaptive response, and learning and memory. In the past, agents that have noradrenergic and/or dopaminergic effects have demonstrated benefit in the treatment of ADHD. Although not approved by the United States Food and Drug Administration (FDA) for treatment of ADHD, antidepressants, particularly the tricyclic antidepressants, have been found to be effective in treating ADHD because of their inhibition of norepinephrine reuptake. However, the risk of serious adverse effects and the availability of alternative agents have tempered the use of tricyclic antidepressants by patients with ADHD or depression. Based on the mechanism of action of the tricyclic antidepressants in the inhibition of norepinephrine reuptake (a noradrenergic component thought to be depleted in the prefrontal cortex of humans with ADHD), the development of newer therapies has focused on increasing the levels of norepinephrine in an attempt to control symptoms of ADHD. Evidence arising from pharmacologic studies targeting the noradrenergic hypothesis has led to the development of an agent that specifically targets the norepinephrine transporter; this agent is atomoxetine.
Atomoxetine (Strattera; Eli Lilly and Co., Indianapolis, IN), a norepinephrine transport inhibitor, was developed as an antidepressant. It now is the first nonstimulant agent approved by the FDA for treatment of ADHD in children and adults. The drug was originally known generically as tomoxetine, but this designation was changed to avoid potential prescribing and dispensing errors due to confusion with similar sounding agents (e.g., tamoxifen).