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Aims: The main purpose of this first atomoxetine study in Japanese adults with attention-deficit/hyperactivity disorder (ADHD) was to investigate the tolerability of an 8-week treatment regimen.
Methods: This was an open-label, dose escalation study conducted in 45 Japanese patients aged at least 18 years with DSM-IV-defined ADHD. Patients received atomoxetine orally for 8 weeks. Atomoxetine administration was started at 40 mg/day (7 days), and subsequently increased to a maximum dose of 120 mg/day. Tolerability was assessed by discontinuation rate due to adverse events. Adverse events, laboratory tests, vital signs and electrocardiograms were collected. In addition, ADHD symptoms were assessed by using the Japanese version of the Conners' Adult ADHD Rating Scale-Investigator Rated: Screening Version (CAARS-Inv:SV) scores.
Results: Thirty-nine patients completed the study period. Atomoxetine was well tolerated with a 6.7% (3/45) discontinuation rate due to nausea, malaise and anorexia. The most commonly reported adverse events were nausea, nasopharyngitis and headache; there were no unexpected safety concerns. No deaths or serious adverse events were reported. Mean CAARS-Inv:SV-J total ADHD symptom scores decreased in a time-dependent manner; the mean change from baseline to endpoint was −15.0 (P < 0.001).
Conclusions: This study showed that atomoxetine was well tolerated in these patients and suggested that atomoxetine at a maximum dose of 120 mg/day would be safe in Japanese ADHD patients.
ATTENTION-DEFICIT/HYPERACTIVITY DISORDER (ADHD) is a chronic neurodevelopmental disorder with onset typically prior to 7 years of age. The predominant symptoms involve problems of inattention, hyperactivity and impulsivity. ADHD had been thought to be a specific disorder of children, and therefore was not considered to be observed in adults for a long time.1 However, multiple lines of research have demonstrated that ADHD is a chronic disorder with onset in childhood that persists into adulthood in 30–80% of all children with ADHD.2–4 Awareness of adult ADHD was low, and ADHD symptoms in adulthood include poor planning and organization, poor memory, difficulty in finishing daily jobs, lower academic achievement, distractibility and restlessness.5,6 Accordingly, some adult patients find it difficult to cope in their work and life. In addition, ADHD is known to be associated with various comorbid disorders.7 Although psychostimulants and atomoxetine are available for adult ADHD patients in some other countries, there is no approved medication for Japanese adult patients.8 Therefore, medication in adults is considered necessary for treatment of ADHD symptoms.
Atomoxetine hydrochloride (hereafter referred to as atomoxetine) is a selective inhibitor of the presynaptic norepinephrine transporter, with little affinity for other neurotransmitter transporters or receptors.9 Atomoxetine is classified as a non-stimulant and has a very low risk of abuse.10
Atomoxetine is known to be metabolized by cytochrome P450 2D6 (CYP2D6) predominantly.11,12 It is reported that few people are classified as poor metabolizers (PM), that is some CYP2D6 gene mutations or deletions associated with defective CYP2D6 metabolism. Shimizu et al. reported that there was racial differences in the frequency of PM on CYP2D6; 1.9% of Asian and 7.7% of Caucasians.13
In a placebo-controlled, double-blind trial of atomoxetine in Japanese children and adolescents with ADHD aged from 6 to 17 years, atomoxetine was shown to be generally well tolerated with no safety concerns.14 Atomoxetine was also found in that study to be effective at reducing ADHD symptoms as shown by decreases in ADHD RS-IV-J:I total score (Attention-Deficit/Hyperactivity Disorder Rating Scale-IV-Parent Version: Investigator-Administered and Scored, translated and validated in Japanese). As of February 2009, atomoxetine has been approved for children and adolescents with ADHD in 84 countries and regions.
While there are a number of studies of atmoxetine treatment in child and adolescent ADHD patients, few studies have been reported in adult ADHD patients. However, these studies have also demonstrated that atomoxetine was safe and efficacious in adults with ADHD15,16 and at present atomoxetine has been approved for adult use in more than 39 countries including the United States. On the other hand, currently there are no data available regarding the safety and efficacy of atomoxetine in Asian adult patients with ADHD.
As a first step in this patient group, the present study investigated the tolerability of atomoxetine in Japanese adults with ADHD to obtain a preliminary assessment of safety in these patients. In addition, changes in ADHD symptoms following atomoxetine treatment were assessed by using the Japanese version of the Conners' Adult ADHD Rating Scale-Investigator Rated: Screening Version (CAARS-Inv:SV-J; Multi-Health System Inc, North Tonawanda, NY, USA).17
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The present study is the first investigation of the tolerability of atomoxetine in Japanese adult ADHD patients. The results suggested that atomoxetine was well tolerated and that it would be safe in these patients. Furthermore, a decrease in CAARS-Inv:SV-J scores was observed following administration of atomoxetine.
Of the 45 patients enrolled in this study, 39 patients completed study period II with 8 weeks of atomoxetine treatment. The discontinuation rate due to adverse events was 6.7%. This was almost similar to the rates, 7.8% and 9.3%, observed in two large-scale, placebo-controlled studies completed in the US in adult ADHD patients.15 In addition, the proportion of compliant patients at each visit was more than 93.2%. These results suggest that treatment with atomoxetine was well tolerated in Japanese adults with ADHD.
There were no unexpected adverse events observed in these Japanese patients. The most commonly reported adverse events were nausea, headache, anorexia and somnolence, all of which have been reported in previous overseas studies with atomoxetine.15,21,22 Statistically significant changes were seen in some laboratory tests, vital signs and ECGs, however, these changes were small and were not considered clinically significant. The increase in heart rate, significant changes in diastolic blood pressure were not unexpected from pharmacologic action of atomoxetine. The Fridericia correction of the QT interval (QTcF) was the preferred method of assessment, and no statistical significance was observed in the mean change from baseline to endpoint in QTcF interval. Michelson et al. reported that no serious safety concerns were observed during a 10-week treatment period in two placebo-controlled, double-blind studies with adult ADHD patients in the US, while modest mean increases in blood pressures and heart rate appeared to be associated with atomoxetine.15 These results suggested that the Japanese adult ADHD patients in this study had a similar safety profile to that seen in US studies with adult ADHD patients. However, further study will be required to investigate tolerability and safety more thoroughly because of the small size and open-label design of this study.
A proportion of PM patients was 2.2% (1/45) in our study. Shimizu et al. reported that racial differences in the frequency of PM on CYP2D6 was 1.9% of Asian and 7.7% of Caucasians.13 From these results, PM frequency in Japanese patients in our study was almost consistent with the previous report and was not unexpected, although the number of patients in our study was small and there is a limitation to interpret these data.
Atomoxetine has been approved for the treatment of children and adolescents with ADHD in Japan in April 2009. In a placebo-controlled, double-blind study in 245 Japanese children and adolescents with ADHD, two patients in the atomoxetine treatment groups discontinued from the study due to adverse events. Importantly, adverse events reported at least 5% of patients were nasopharyngitis, headache, decreased appetite, somnolence and nausea, vomiting, abdominal pain and diarrhea.14 There were no major differences in the safety profiles between the Japanese adult ADHD patients in this study and Japanese pediatric ADHD patients reported in the previous study.
This study also took a preliminary look at how ADHD symptoms changed in these patients during a course of atomoxetine administration. Symptoms were evaluated by using a Japanese version (CAARS-SV-J) of the Conners Adult ADHD Rating Scale-Screening Version (CAARS-SV). Treatment with atomoxetine for 8 weeks showed statistically significant decreases in CAARS-Inv:SV-J total ADHD symptoms scores in a time-dependent manner from baseline to the last observational visits. This result was similar to previous studies showing that atomxetine improved ADHD symptoms in adults as measured by CAARS-Inv:SV-J total score.15,20 Although further study to evaluate ADHD symptoms in Japanese adults will be required, these results suggest that atomoxetine would be expected to be efficacious and safe in Japanese adults with ADHD as has been shown in other countries.
Since this was an open-label study with a small number of patients and a limited treatment period, the results of efficacy and safety in this study was suggestive for treatment with atomoxetine in Japanese adult patients, however, we can not conclude definitely, Therefore, safety and efficacy need to be confirmed in a larger scale, placebo-controlled study in Japanese adult patients with ADHD. Such a study, along with a long-term treatment study, is now being conducted to achieve these objectives.