In a recent meta-analysis «Schwartz S, Correll CU. Efficacy and safety of ato...»1 efficacy and safety of atomoxetine (ATX) compared with placebo in the treatment of children and adolescents. Study inclusion criteria were as follows: ATX monotherapy versus placebo; double blinded randomized controlled design; primary ADHD of any type, with oppositional defiant disorder (ODD), anxiety, and depression comorbidities allowed; patient age < 18 years; patient IQ of > 75. The primary outcome measure was baseline to end-point change in parent-rated, 18-item ADHD efficacy scale (ADHD-RS IV P/I), Swanson, Nolan, and Pelham rating scale-revised-IV ADHD (SNAP-RS IV ADHD), ADHD-RS Japanese version, investigator-administered (ADHD-RS J/I Total) or Parent/Investigator ADHD checklist score. Data from the safety outcomes were also extracted.
Altogether 25 RCTs, with 3 928 participants were included in the analysis. The mean follow-up time was 8.6 weeks (range: 4 – 18 weeks). The average ATX dose was 1,17 mg/kg/day. Mean age was 10,3 years, with 68,2 % being <13 years old. Altogether, 51,3 % were anti-ADHD medication naïve, and 44,6 % had comorbid ODD/CD.
All-cause discontinuation with ATX was like that of placebo. However, ATX had higher discontinuation rate due to adverse effects (AEs) (RR = 1,89; CI 95 % = 1,08 – 3,31; p=0,03). At least 1 AE (70,4 % versus 56,1 %; p<0,01) and at least 1 psychiatric AE (21,5 % versus 7,4; p<0,01) were more frequent with ATX. The most common AEs associated with ATX were gastrointestinal symptoms, including vomiting, abdominal pain, nausea and diarrhea (22,1 % versus 12,4 %; p<0,0001), nervous system symptoms, including dizziness, headache, somnolence, sedation and drowsiness (21,8 % versus 15,2 %; p<0,0001), anorexia (19,2 % versus 5,2 %; p<0,0001) and fatigue (11,7 % versus 4,6 %; p<0,0001). Serious AEs (1,5 % versus 1,0 %, NS), aggression (7,5 % versus 6,0 %; NS), depression (2,9 % versus 6,0 %, NS), insomnia (7,1 % versus 6,8 %; NS) and suicidal ideation (1,3 % versus 0,9 %; NS) were not different from placebo.
Compared to placebo, patients with ATX treatment had an increase in diastolic BP (2,5 mmHg; CI 95 % 1,8 to 3,1; p<0,0001), systolic BP (1,5 mmHg; CI 95 % 0,6 to ,3; p<0,001), and heart rate (6 beats per minute; CI 95 % 5 to 7; p<0,0001). They also had decreased body weight (-1,4 kg; CI 95 % -1,1 to -1,8; p<0,0001) and shorter QTc on ECG (-12,8 ms; CI 95 % -9,0 to -16,2; p<0,0001).
A review and network meta-analyses (NMA) published in Lancet Psychiatry 2018 «Cortese S, Adamo N, Del Giovane C, ym. Comparative...»2 compared efficacy and tolerability (proportion of patients who dropped out of studies because of side-effects) of medications for attention-deficit hyperactivity disorder in children, adolescents and adults. The methodical quality of the NMA was good. 81 double-blind randomised controlled trials comparing amphetamines, atomoxetine (ATX), buprobion, clonidine, guanfacine, methylphenidate and modafinil with each other or with placebo in the treatment of ADHD in children and adolescents were included. The exact number of studies comparing ATX with placebo in the treatment of ADHD in children and adolescents was not reported. However, from the figure (Figure 2) it can be concluded that many of those included RCTs compared either ATX or methylphenidate with placebo. No significant difference in tolerability were noted between atomoxetine and placebo in children and adolescents.
Comment: In rare cases, treatment with atomoxetine has been associated with liver damage manifested by elevated liver enzymes and bilirubin levels and associated jaundice. Very rarely, severe liver damage has also been reported, including acute liver failure. Treatment with Atomoxetin should be discontinued in patients with jaundice or liver damage based on laboratory tests and in these cases treatment should not be restarted.