Aggression, Mania, and Hypomania Induction Associated With Atomoxetine (2004)

To the Editor.—Atomoxetine is a selective inhibitor of norepinephrine reuptake recently approved for the treatment of attention-deficit/hyperactivity disorder (ADHD). In 4 double-blind, placebo-controlled clinical trials leading to Food and Drug Administration approval, ∼70% of child and adolescent subjects responded based on reductions in scores on a variety of measures for ADHD symptomatology.1,2 Although no major risks were identified in these trials, a small percentage of subjects seem to have experienced mood destabilization. Irritability was reported in 8% of subjects, and mood swings were observed in 2% of subjects. Four subjects discontinued the drug because of irritability or aggression.3 Our clinical experience has been that mood destabilization is a much more prevalent risk than was observed in the above-mentioned clinical trials. Indeed, the literature contains a case report of the same molecule (under the name tomoxetine) inducing mania in an adult.4Our pooled data include 153 sequential patients (10.5 ± 3.74 years old) treated with atomoxetine in outpatient settings in Denver, Colorado, and North Branch, Minnesota (see Table 1). We have observed extreme irritability, aggression, mania, or hypomania induction in 51 cases (33%). Of those 51 cases, 31 (61%) had a positive family history for mood disorders. Forty-one patients (80%) had a personal history of mood symptoms. Both a personal history and a family history of mood swings were present in 27 cases (53%). Thus, either a personal or family history of mood instability was strongly associated with an increased likelihood of mania/hypomania induction or mood dysregulation. Of great concern, the risk of mood dysregulation with atomoxetine does not seem to be limited to cases with histories of mood symptoms. Six of the 51 cases (11%) had no personal history of mood instability or family history of bipolar disorder. Thus, it will be important to monitor all patients treated with this medication closely.The diagnosis of mania or hypomania was not based solely on distractibility, motoric hyperactivity, or talkativeness. Irritability, aggression, and grandiose defiance were the most frequently observed symptoms. The majority of cases did not demonstrate hyperactivity concurrent with these mood symptoms. Ten patients developed symptoms severe enough to be considered mania, and 3 of those were hospitalized (see ref 5 for a detailed description of 1 such case), whereas 3 others were incarcerated in juvenile detention centers.The onset of aggressive and/or mood symptoms occurred at 6.39 ± 5.36 weeks after starting atomoxetine. There was no significant difference between time to onset of symptoms in patients who also were treated with mood stabilizers (5.95 ± 5.68 weeks, N = 22) or atypical antipsychotics (5.88 ± 5.22 weeks, N = 26). Similarly, resolution of symptoms was independent of the presence or absence of other pharmaceutical agents (1.72 ± 1.20 weeks).One possible explanation for increased irritability and aggression in these cases is incompletely treated ADHD with its attendant impulsivity. However, a number of patients in this series were either transitioned from stimulants or augmented with stimulants during their course of treatment with atomoxetine, which made it feasible to separate the hyperactivity out from the apparent mood symptoms. Augmentation with a stimulant frequently led to resolution of hyperactivity while the symptoms of irritability, moodiness, and/or aggression would remain. It is unclear why we are seeing a higher rate of mood destabilization compared with the clinical trials.2,3 Age was not a factor, because the mean age of patients who experienced mood dysregulation was not significantly different from that of the total sample. Furthermore, cotreatment with mood stabilizers or atypical neuroleptics did not prevent mood dysregulation in a substantial portion of the cases. Cross-tapering from a stimulant was also not correlated with this adverse effect, because 32% of the cases in which mania or hypomania occurred were not being treated with stimulants before or during treatment with atomoxetine.Our collective experience argues that caution should be used in selecting atomoxetine as a treatment in children with a personal history of mood dysregulation or mood disorder or who have a family history of mood disorders. Moreover, mania/hypomania induction or mood dysregulation can occur in a percentage of patients (4% of our total sample) who have no family or personal risk factors for mood disorder.