Edivoxetine (LY-2216684): A Comprehensive Monograph on a Selective Norepinephrine Reuptake Inhibitor – From Pharmacological Promise to Clinical Discontinuation

Executive Summary

Edivoxetine, also known by its development code LY-2216684, is a small molecule drug developed by Eli Lilly and Company as a potent and highly selective norepinephrine reuptake inhibitor (NRI).[1] Its primary mechanism of action is the specific blockade of the norepinephrine transporter (NET), leading to increased synaptic concentrations of norepinephrine.[3] This mechanism formed the therapeutic rationale for its investigation in two major psychiatric conditions: as an adjunctive treatment for Major Depressive Disorder (MDD) in patients with a partial response to selective serotonin reuptake inhibitors (SSRIs), and as a monotherapy for Attention-Deficit/Hyperactivity Disorder (ADHD).[1]

Despite a promising pharmacological profile and evidence of target engagement in humans, the clinical development program for Edivoxetine ultimately met with definitive failure. The extensive Phase III program for MDD, comprising three large, randomized, placebo-controlled trials, failed to demonstrate that Edivoxetine, when added to an existing SSRI, provided any statistically significant benefit over adding a placebo.[5] This lack of efficacy was observed despite the drug demonstrating a clear biological effect, as evidenced by its characteristic noradrenergic safety profile.

The safety and tolerability profile of Edivoxetine was consistent with its mechanism of action, characterized by statistically significant increases in blood pressure and heart rate, as well as common noradrenergic side effects such as hyperhidrosis, nausea, and dry mouth.[7] While these effects were generally manageable, they underscored that the drug was pharmacologically active.