Abstract: Drugs that affect neurotransmitter release can induce changes in neuroregulation during chronic administration. Thus, in addition to recurrence of symptoms of the illness, discontinuation of treatment can be associated with clinical signs and symptoms related to these changes. Atomoxetine, a new drug approved in the United States for treatment of attention deficit/hyperactivity disorder (ADHD), is associated with blockade of the presynaptic norepinephrine transporter. Because treatment of ADHD typically involves chronic treatment, the potential for production of a discontinuation syndrome as well as recurrence of symptoms upon drug discontinuation were assessed as part of the clinical development process. The effects of discontinuation of atomoxetine were assessed in children and adults with ADHD following 9 to 10 weeks of continuous therapy in 4 large studies. Symptoms of ADHD worsened following drug discontinuation but did not return to pretreatment levels. The incidence of discontinuation-emergent adverse events was low and there were no statistically significant differences between the patients abruptly discontinuing from atomoxetine and those continuing on placebo. Discontinuation of atomoxetine did not result in the development of an acute discontinuation syndrome and was well tolerated. It appears that atomoxetine may be discontinued without risk for symptom rebound or discontinuation-emergent adverse effects. Tapering of doses is not necessary when atomoxetine is discontinued.
Upon discontinuation of a drug, 2 clinical issues are important: recurrence of symptoms and a possible discontinuation effect. Although pharmacotherapy leads to physiologic changes, these usually do not persist indefinitely after drug discontinuation. Thus, it is important for clinicians and patients to know when decline in efficacy may be expected upon discontinuation of a drug. Further, discontinuation of drug therapy following an extended period of administration is often associated with the emergence of new, typically unwanted signs and symptoms.1,2 Such discontinuation syndromes, while sometimes including features of the disorder for which the drug was originally prescribed, can also include other signs and symptoms. They typically do not represent a relapse or recrudescence of the underlying condition, but rather are probably related to the disruption of neuroregulatory changes established during drug administration. Much has been written about stimulant medication and the exacerbation of behavioral symptoms following discontinuation of medication; however, there are very few controlled studies examining these effects. A naturalistic study of hyperactive boys demonstrated a rebound effect of increased motor activity upon discontinuation of dextroamphetamine use compared with placebo.3 The specific symptom profiles of discontinuation syndromes depend on the pharmacology and pharmacokinetics of the drug being administered and vary in severity and timing.3
Drugs used for the treatment of psychiatric disorders typically act by altering neurotransmission at specific central nervous system receptors and are commonly administered for periods of several months to years. As a result, many of these drugs have the potential for unwanted effects related to interruption or discontinuation of treatment. Because many patients miss doses during treatment or stop treatment without consulting their physician, discontinuation syndromes can be clinically important, particularly if they are not recognized and their signs and symptoms are incorrectly attributed to recrudescence of the disorder for which the drug was originally prescribed. In recent years, clinicians have become increasingly aware of the potential for some drugs to cause discontinuation syndromes, and regulatory agencies have begun to require characterization of effects related to discontinuation during the development process for new drugs.
Atomoxetine, a highly specific inhibitor of the norepinephrine transporter (Ki ~ 4.5 nM) with little affinity for other transporters or neurotransmitter receptors, is approved in the United States for the treatment of attention deficit/hyperactivity disorder (ADHD). Atomoxetine has a half-life of about 5 hours and is eliminated primarily by oxidative metabolism through the Cytochrome P450 2D6 enzymatic pathway and subsequent glucuronidation. It is rapidly absorbed after oral administration, and maximal plasma concentrations (Cmax) are reached approximately 1 to 2 hours after dosing. A growing body of published data has provided evidence of atomoxetine's efficacy and safety, but to date, effects following discontinuation have not been reported.4-6 As treatment in ADHD typically lasts for months or years, it is likely that many patients will receive atomoxetine for extended periods. However, it is also likely that some patients will periodically want to suspend treatment for fixed periods (eg, during vacations), and particularly among older children, there may be episodes of noncompliance related to developmental issues, such as needs for control and autonomy. For these reasons, it is important for clinicians to have information about the effects of abrupt discontinuation of atomoxetine. We present here data from a series of studies in which atomoxetine was discontinued under controlled conditions to assess its potential for causing a discontinuation syndrome.