Raynaud's Phenomenon Related with Atomoxetine Treatment in a Child with Autism and Attention-Deficit/Hyperactivity Disorder

Case Presentation

B. is a 7-year-old boy with ASD presented with his mother due to behavioral problems, including hyperactivity, impulsivity, and aggressive behaviors toward his peers. His current psychiatric examination confirmed diagnosis of ASD and ADHD. His weight was 23 kg and he was started ATX 10 mg/day as 0.5 mg/(kg·d) dose basis at morning that was increased to 18 mg/day after 1 week. Two weeks later, no significant side effects were reported and ATX was titrated to 28 mg/day. Two days later starting ATX 28 mg/day, the mother reported, on a phone call, that he had bilateral digital pallor and cooling and circumoral cyanosis that emerged 1 hour later with the first dose of ATX 28 mg/day and lasted for 2 days. Consultation was sought with pediatric rheumatologist as RP was suspected. Consultation revealed that there was bilateral peripheral pallor on examination of upper limbs and the rest of the physical examination was normal.

There was no history of cyanosis on hands related to cold exposure, arthritis, arthralgia, xerostomia, xerophthalmia, and photosensitivity. The mother denied the use of any drug, herbal product, or substance. There was no family history of rheumatologic disease and no consanguinity between parents. The patient's antinuclear antibody screening, erythrocyte sedimentation rate, and anticomplement C3 and C4 antibodies were within normal limits or unremarkable. RP was diagnosed by a pediatric rheumatologist and no underlying pathology was identified. Discontinuation of ATX was recommended and his symptoms resolved.

Discussion

RP is a transient cessation of blood flow, affecting digits of the hands and feet (Cooke and Marshall 2005). RP is often associated with stress, cold exposure (80%–90%), and various autoimmune or other systemic diseases and conditions (Khouri et al. 2016). In addition to these conditions, some drugs are found to be causing medication-induced RP (Khouri et al. 2016). ATX is a nonstimulant, well-tolerated, and relatively safe treatment option for ADHD (Kratochvil et al. 2003). To the best of our knowledge, Gokcen et al. (2013) reported the only ATX-induced RP in the literature. According to the report, a 10-year-old girl developed RP soon after a dosage increase and symptoms disappeared when the medication was stopped (Gokcen et al. 2013). Similar to the previous report, in our case, RP emerged immediately after ATX was increased to 28 mg/day and the symptoms had improved after discontinuation of ATX.

In our case, unlike the previous report, symptoms did not disappear in a few hours but lasted a whole day long. Assessment with Naranjo Adverse Drug Reaction Probability Scale revealed a score of 8 that shows probable adverse drug reaction (Naranjo et al. 1981). Although the pathogenesis is not fully evident yet, the key mechanisms could include vascular, neural, and intravascular factors (Cooke and Marshall 2005). We suggest that an increase of norepinephrine and dopamine release through the catecholaminergic system may be prominent as they are thought to cause RP by inducing vasoconstriction in peripheral vessels (Cooke and Marshall 2005).

Several reports of RP with reboxetine (a norepinephrine reuptake inhibitor) (Bertoli et al. 2003) and development of peripheral gangrene as a result of direct infusion of catecholamines (Sama et al. 2016) may be in line with this hypothesis. Given the previous study and our experience with this case, ATX may cause a peripheral release of catecholamines by increasing norepinephrine and dopamine level in the central nervous system, leading to vasoconstriction in peripheral tissues and thus symptoms of RP. Although RP is a rare adverse effect, clinicians should be careful during ATX treatment as it may lead to treatment noncompliance and physical health risks particularly in individuals with limited verbal and/or mental capacity.