Edivoxetine Hydrochloride

The use of first-line drugs in clinical practice for attention deficit hyperactivity disorder (ADHD) is limited by their adverse effects. Many novel monoamine reuptake inhibitors (MRIs) with better safety profiles and comparable efficacy are also being tried for ADHD. This network meta-analysis (NMA) has evaluated the efficacy and safety of MRIs in ADHD. The data was extracted from 31 relevant clinical trials after a literature search on MEDLINE/PubMed, Embase, Scopus, Cochrane databases, and clinical trial registries. Quality assessment was performed using the risk of bias assessment tool (RoB2) by Cochrane Collaboration, and the random-effects model was used to estimate the effect size. Standardised mean difference (SMD) and 95% credible interval(95%CrI) were reported for the reduction in ADHD rating scale score. Network geometry was visualised, and node splitting was done for the closed triangles. Meta-regression was done for the duration of therapy. PRISMA-NMA guidelines were followed in selecting, analyzing, and reporting findings. The drugs showing significant reduction on the ADHD rating scale as compared to placebo are bupropion (SMD: 0.33; 95%CrI: 0.60,-0.059), dasotraline(SMD: 0.49; 95%CrI: 0.82,-0.16), venlafaxine(SMD: 0.71; 95%CrI: 1.3,-0.15), viloxazine(SMD: 0.45; 95%CrI: 0.77,-0.12). Other drugs (centanafadine, duloxetine, edivoxetine, reboxetine, tipepidine, vortioxetine) were no better than placebo in reducing symptom severity of ADHD. The efficacy of none of the drugs was found to be significantly different as compared to methylphenidate. Among all, duloxetine (OR:15; 95%CrI:1.8130) showed significantly more treatment-emergent adverse events than methylphenidate. In conclusion, venlafaxine, viloxazine, and bupropion are the most efficacious MRIs for ADHD symptom reduction as compared to placebo with high certainty of evidence.

The purpose of this study was to assess the long-term safety and tolerability of edivoxetine, a selective norepinephrine reuptake inhibitor, which was being developed as monotherapy in pediatric attention-deficit/hyperactivity disorder (ADHD).

This was an open-label study of edivoxetine once daily dosing (0.1-0.3 mg/kg) as treatment for ADHD in children (6-11 years) and adolescents (12-17 years) to assess safety for up to 5 years. The safety assessments included the incidence of adverse events, vital signs, electrocardiograms, laboratory tests, percentile changes in weight, height, and body mass index, and Tanner staging. Efficacy of treatment with edivoxetine was also assessed using the Attention-Deficit/Hyperactivity Disorder Rating Scale-Version IV-Parent Reported: Investigator Scored (ADHDRS-IV) and Clinical Global Impressions-ADHD-Severity (CGI-ADHD-S).

A total of 267 children and adolescents were enrolled and 20 completed the 5-year study. Most of the participants were male (70.4%) and white (67.4%), and the mean age was 11.6 years. Two hundred three participants (76.9%; N = 264) experienced at least one adverse event. Treatment-emergent adverse events reported in >10% of participants were headache, vomiting, nausea, and upper respiratory tract infection. Serious adverse events (SAEs) were reported by seven participants (2.7%) during study treatment periods, and one participant was diagnosed with suspect epilepsy during the follow-up period after discontinuation of edivoxetine.

Long-term open-label treatment with edivoxetine as monotherapy in children and adolescents with ADHD revealed a safety profile that was consistent with its pharmacological effects on norepinephrine transmission and with that reported in short-term studies of edivoxetine. The study was terminated early due to slow enrollment and the very low number of 5-year completers. Lilly is not proceeding with further development of edivoxetine, as announced in 2013.