Abstract
To The Editor:
T
Case Report
An 8-year-old boy had been diagnosed at 6 years of age with ADHD, combined type, and chronic motor tic disorder, according to the Diagnostic and Statistical Manual of Mental Disorders, 4th ed., Text Revision (DSM-IV-TR) criteria (American Psychiatric Association 2000). His older sister had ADHD with comorbid Tourette's disorder. The patient had received atomoxetine 25 mg/day (1.1 mg/kg/day) for ADHD, and aripiprazole 10 mg/day for tic disorder, with obvious clinical improvement. At age 7, atomoxetine was increased to 40 mg/day (1.7 mg/kg/day) because the patient was inattentive and impatient doing homework, in addition to exhibiting hyperactive symptoms such as hopping around and fidgeting in class. After 3 weeks of increasing doses, the patient developed AH: A male voice calling his name. He responded to it frequently by turning his body, walking toward the voice, gesturing, and talking back. Elevated and irritable mood, decreased need of sleep, excessive talking, racing thoughts, and frequent arguments with classmates were also noted. Atomoxetine was decreased to 25 mg/day, with aripiprazole maintained at 10 mg/day, and the manic symptoms, and AH gradually subsided within 2 weeks.
At age 8, atomoxetine was increased to 25 mg/40 mg every other day for ADHD symptoms of inattention, “fooling around,” and completing assignments slowly at school and at home. After the dosage adjustment, ADHD symptoms improved without obvious side effects. Six months later, the patient's parents accidentally increased the dose to 40 mg every day, and once again, manic-like symptoms including being hypertalkative, and having increased thought content and a decreased need of sleep developed within 2 weeks. However, no AH were noted this time. Atomoxetine was shifted back to 25 mg/40mg every other day and the abovementioned symptoms resolved within 1 week.
Because of the development and resolution of psychotic symptoms closely followed the increasing and decreasing of atomoxetine dosage, atomoxetine-induced mania and AH were highly suspected.
Discussion
This 8-year-old boy is the youngest case of atomoxetine-induced mania and AH ever reported. Atomoxetine is a norepinephrine reuptake inhibitor and exerts its therapeutic effect by increasing norepinephrine concentration in the brain (Christman et al. 2004). However, norepinephrine hyperactivity has also been postulated as a potential mechanism inducing mania (Bhanji et al. 2002). In addition, because of the structural similarity between norepinephrine and dopamine, the norepinephrine transporter may reuptake dopamine as well (Moron et al. 2002). By inhibition of this presynaptic norepinephrine transporter, atomoxetine may increase extracellular dopamine level in the brain (Swanson et al. 2006) and induce psychotic symptoms in susceptible individuals.
Further inquiry revealed that the patient's older sister had also experienced mania-like symptoms with irritability and verbal aggression after treatment with atomoxetine. Family history or personal history of mood disorders or medication-induced mood instability may be an important risk factor for atomoxetine-induced mania, as has been pointed out by previous reports (Henderson 2004; Bahali et al. 2013). Patients with ADHD in childhood and adolescence have increased risk of bipolar disorder or schizophrenia later in life (Dalsgaard, et al. 2014; Dalteg et al. 2014), and this may be because of some shared genetic factors among these disorders (Larsson et al. 2013). Patients who have inherited with these genetic vulnerabilities may, therefore, have a higher risk of drug-induced manic or psychotic symptoms during atomoxetine treatment for ADHD.
Two major differences regarding pharmacotherapy between previous case reports and ours should be noted. First, our patient had been given regular doses of aripiprazole to control his motor tic symptoms continuously since age 6, and no dosage adjustments were made prior or during the two episodes of atomoxetine-induced mania. None of the previously reported patients had received antipsychotics at the same time. This finding showed that atomoxetine could induce psychotic symptoms such as mania or AH even in patients already taking antipsychotics, and it highlighted the importance of careful monitoring of psychotic symptoms during atomoxetine treatment regardless of concurrent antipsychotic use.
Second, atomoxetine-induced psychosis or mania in previously reported adolescent cases were managed by total discontinuation of the medication (Henderson 2004; Tang et al. 2009; Bahali et al. 2013; Guney and Uneri 2014). In contrast, the psychotic symptoms of our case resolved completely after we tapered down atomoxetine dosage instead of discontinuing it totally. And the beneficial effect of atomoxetine for the patient's ADHD symptoms was still observed afterwards. This indicated that atomoxetine-induced psychotic symptoms may be dose related, and that atomoxetine may still be used effectively to treat ADHD with careful dose adjustment.
In conclusion, psychiatrists should pay attention to emerging psychotic symptoms during initiation or dose adjustment of atomoxetine. Instead of total discontinuation, tapering down atomoxetine dosage alone could adequately control this adverse effect.
Disclosures
No competing financial interests exist.