Abstract
To the Editor:
Case Report
We present a case of a 12-year-old Caucasian girl with ADHD, combined type, who had been stable on extended release amphetamine/dextroamphetamine salts (Adderall XR® 10 mg) for the previous 1.5 years. Because of concern about the patient's low weight gain and persistent complaint of “feeling numb” on Adderall, it was planned to switch to atomoxetine. Her Adderall dose was decreased to 5 mg and she was started on atomoxetine 10 mg/day. Five days later, her dose of atomoxetine was increased to 18 mg/day and on day 10, the dose was further increased to 25 mg/day. On day 12, the patient started complaining of severe anxiety and subjective restlessness, and she expressed a constant need to move. She was pacing around and was very agitated. The Barnes Akathisia Rating Scale score was 8 out of 9, and on global clinical assessment, severe akathisia was indicated. Recent medication changes, substance use, or over-the- counter medication use were ruled out clinically. Atomoxetine and Adderall were discontinued. The patient's symptoms resolved completely 4 days after discontinuing both Adderall and atomoxetine. At the time of follow-up, the Barnes Akathisia Rating Scale score was 1 out of 9 and the family reported significant improvement. After 2 weeks of drug holidays the patient was started on methylphenidate 18 mg/day for ADHD and tolerated that medication without any side effects. We postulate that atomoxetine was the causative agent here, because of the temporal onset of akathisia after introducing atomoxetine to the Adderall, as the patient had already been taking Adderall 10 mg for the previous 1.5 years and the dose had also been decreased to 5 mg at the time of starting her on atomoxetine.
Discussion
“Atomoxetine-induced akathisia” has never been reported in the literature. Drug- induced akathisia has been reported with all conventional and atypical antipsychotics, tricyclic antidepressants, selective serotonin reuptake inhibitors (SSRIs), venlafaxine, mirtazapine, lithium, and antiemetics (Koliscak and Makela 2009). The exact pathophysiology of the drug-induced akathisia is unknown; the most acceptable hypothesis is postsynaptic dopaminergic blockade in the mesocortical pathway. The ventral tegmental area (VTA) contains the cell bodies of mesocortical dopaminergic (DA) systems (Lipinski et al. 1989). In the animal model, high frequency bilateral lesions in the VTA induced akathisia-like syndrome in the rat, characterized by a permanent locomotor hyperactivity and a reduction of attention capacities (Tassin et al. 1978). Noradrenergic and serotonergic-mediated inhibition of the dopamine transmission in the mesocortical pathway projecting from the VTA to the prefrontal cortex has been reported. It has been proposed that drugs that increase the stimulation of noradrenergic and serotonergic receptors in the mesocortical pathway can induce akathisia (Lane 1998), which would, therefore, theoretically explain the atomoxetine-induced akathisia. This proposed mechanism has been further supported by the fact that drugs such as propranolol, which have been used to treat akathisia, have been found to increase the dopamine in the mesocortical pathway (Lane 1998).
Adderall and atomoxetine are both metabolized by the same CYP2D6 in the liver, and neither of them has any inducers and inhibitory properties at the CYP level (Sauer et al. 2005). In the literature, no drug–drug interaction has been reported between Adderall and atomoxetine. Therefore, it is unlikely that any pharmacokinetic interaction has contributed to the akathisia presentation in this case. Clinicians should be aware of akathisia associated with atomoxetine treatment, and should monitor closely for symptoms of akathisia when starting this medication.
Footnotes
Disclosures
No competing financial interests exist.