Abstract
To the Editor:
Raynaud's phenomenon (RP) is defined as paroxysmal vasospasm in fingers in cases of cold or emotional stress. Patients complain of pain associated with sudden pallor and/or cyanosis in distal two thirds of their fingers. This condition is usually idiopathic, and females account for 60–90% of the cases (Jaffe 1995). RP emerging in association with scleroderma, CREST (calcinosis, RP, esophagus dismotility, sclerodactyly, telangiectasia), vaso-occlusive diseases, vibrating tools, or drug use is secondary RP (Towheed and Dewar 1996). In the literature, RP cases occurring from drugs such as citalopram, methylphenidate, dextroamphetamine, yohimbine, and vincristine have been reported (Johnson et al. 2003; Gootschling et al. 2004; Peiro et al. 2007; Syed and Moore 2008). In the present report, a case of RP thought to arise in a dose-dependent manner in a patient with the diagnosis of ADHD, who was administered atomoxetine treatment, is presented.
Case Report
A 10-year-old girl with problems such as hyperactivity at school, communication problems with the family and peers, and school underachievement, whose teacher stated that the child was hyperactive in class and during breaks and had difficulty in learning reading and writing because of lack of attention, was referred with her family to the child psychiatry outpatient clinic. After a psychiatric evaluation and family interview, the girl was diagnosed with ADHD according to American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders, 4th ed. (DSM IV) diagnostic criteria, and atomoxetine 10 mg (0.5 mg/kg/day) was commenced (American Psychiatric Association 1994). At the control visit 1 week later, no side effects were observed, and treatment dose was increased to 18 mg (0.9 mg/kg/day). After the increase in dose, the family was referred to the outpatient clinic again because the girl had complaints of feeling cold associated with ecchymosis in the feet and hands, which started half and hour after drug intake and lasted for 1–2 hours. Then, the dose of atomoxetine was adjusted again to 2×10 mg/day. At the control visit 1 week later, coldness and ecchymosis in the feet and hands had improved, but complaints such as being unwilling to go to school, immobility, and lack of appetite had begun. Atomoxetine was replaced with OROS methylphenidate at a dose of 18 mg/day and the patient was scheduled for a control visit 1 week later. At the visit, it was discovered that complaints of motor tics, numbness in tongue, and trembling in jaw had begun and it was decided to discontinue OROS methylphenidate and resume atomoxetine at a dose of 10 mg/day. When the dose of the drug was increased to 18 mg/day 1 week later, complaints of feeling cold in the feet and hands, and ecchymosis, had started again. At the physical examination made at ambient temperature, necrosis, calcinosis, and ulceration were not observed, and there was coldness in the feet and hands. In the examination made in the rheumatology department, symptoms of photosensitivity, morning stiffness, arthralgia, myalgia, alopecia, recurrent fever, fatigue, and Sjögren syndrome were not present, and in view of present findings, the patient's condition was diagnosed as RP. The results of the laboratory investigations were as follows: Whole blood count was normal, sedimentation 10 mm/hour, C-reactive protein (CRP) 3 mg/dL, rheumatoid factor (-), antinuclear antibody (-), anticentromere antibody (-) and antitopoisomerase (SCL-70) (-). In the child herself and her family, there was no history of collagen tissue disorders, vasculitis, or antiphospholipid syndrome. In order to exclude peripheral vessel diseases, Doppler ultrasonography (USG) examination was performed. Before and after the administration of single dose atomoxetine (18 mg), Doppler USG examination was made in the subclavian, axillary, brachial, radial, and ulnar vessels, and no significant difference was found in blood flow. In addition, the patient was evaluated in the pediatric cardiology department, and electrocardiogram (ECG) and echocardiography examinations yielded normal results and no cardiac pathology was found. No pathology was found in the patient, and the use of atomoxetine at a dose of 10 mg/day was planned. At the control visit the third week after treatment, when marked improvement was seen in ADHD symptoms and RP was not observed, treatment was maintained with 10 mg/day atomoxetine.
Discussion
Atomoxetine inhibits presynaptic norepinephrine transportation with minimal affinity for other neuronal signaling pathways. Deregulated catecholaminergic neurotransmission including dopamine and norepinephrine in the prefrontal cortex is thought to be associated with the pathogenesis of ADHD (Bymaster et al. 2002). Therefore, atomoxetine-induced synaptic and extracellular norepinephrine levels lead to alleviation of ADHD clinical symptoms such as inattention. It is of note that, side effects reported in association with the use of atomoxetine include stomachache, vomiting, headache, constipation, nausea, decrease in appetite, depressive mood, irritability, cardiac murmur, prolongation of QT interval, hypertension, tachycardia, and Wolf–Parkinson–White syndrome (Vitiello 2008; Donnelly et al. 2009; Jiao et al. 2009). Although no case of RP caused by atomoxetine has been reported in the literature so far, RP cases associated with the use of citalopram, methylphenidate, dextroamphetamine, yohimbine and vincristine have been reported (Johnson et al. 2003; Gootschling et al. 2004; Peiro et al. 2007; Syed and Moore 2008).
The fact that the results of clinical examination, laboratory investigations, and radiological findings were normal, and that there was no history of drug use except atomoxetine, led us to rule out other secondary conditions, which may cause RP. In addition, the emergence of coldness and ecchymosis in hands and feet after the increase in dose, impairment in the clinical picture with the discontinuation of drug or decrease in dose, recurrence of the same symptoms with the resumption of drug and increase in drug dose, suggest that this condition is a side effect of atomoxetine.
The recommended starting dose of atomoxetine is 0.5 mg/kg in the mornings. If there is no significant side effect, graduated dose increase with 10 day intervals is recommended at doses of 0.8, 1.0, and 12 mg/kg (Turgay 2006). Therefore, treatment was initiated at the dose of 10 mg/day and 1 week later; the dose was increased to 18 mg/day. However, following the intake of the drug, complaints of coldness and ecchymosis in the hands and feet were observed. It is reported that in patients who cannot tolerate the dose, the drug can be administered in divided doses (Jain et al. 2006; Turgay 2006). Based on this, the daily dose was adjusted again as 2×10 mg. However, this regime led to complaints of unwillingness to go to school, immobility, and lack of appetite. Peripheral coldness did not occur with the divided dose, which was interesting.
When OROS methylphenidate 18 mg/day was initiated instead of atomoxetine, side effects appeared and atomoxetine was resumed at a dose of 10 mg/day and at the control visit 3 weeks later, improvement in symptoms was seen without any side effects. Importantly, atomoxetine exerts its effect by increasing the levels of dopamine and noradrenaline via the inhibition of norepinephrine transporters in the prefrontal cortex (Zhou 2004). Although the pathological mechanisms of RP developing from the use of atomoxetine are not completely known, in a study evaluating the relationship between the use of stimulants and RP in children, it was reported that this might be related to sympathomimetic noradrenaline and dopamine signaling (Goldman et al. 2008). Hence, atomoxetine may lead to impaired re-dilatation of cutaneous vessels after vasoconstriction, even though the mechanism of this effect is not identified completely. One possible explanation is that atomoxetine induces increased levels of noradrenaline in peripheral and central synapses, promoting the stimulation of peripheral α-1 and α-2 receptors, which leads to prolonged vasoconstriction. Similarly, peripheral ischemia and RP were reported following treatment with tricyclic antidepressants and reboxetine, which could be the result of their inhibitory effect on noradrenaline reuptake (Anderson and Morris 1988; Clark et al. 2003).
As far as we know, this is the first case of RP reported in the literature to occur because of atomoxetine use. It is of note that an important question remains to be answered: The incidence of atomoxetine causing rheumatological side effects such as RP in children. To answer this question, further controlled studies with a larger patient population are needed.
Footnotes
Disclosures
No competing financial interests exist.