JAMA Netw Open

Novel SNRI shows favorable safety profile in major depressive disorder

September 29, 2025

Ammoxetine, a structurally modified SNRI derived from duloxetine to reduce hepatotoxicity, demonstrated robust antidepressant effects with a favorable safety profile, including reduced hepatotoxicity compared with duloxetine. These findings support further investigation in phase 3 trials and suggest ammoxetine may offer a more tolerable SNRI option for patients with major depressive disorder (MDD).

Study details: Ammoxetine was evaluated in a multicenter, randomized, double-blind, placebo-controlled trial (NCT05762458) in adults with MDD. Participants received ammoxetine 40 mg/day, 60 mg/day, or placebo for 8 weeks. Primary endpoint was change in Montgomery-Åsberg Depression Rating Scale (MADRS) score from baseline.

Results: Both ammoxetine doses significantly reduced MADRS scores compared with placebo (LS mean difference: −3.3 for 40 mg/day and −3.1 for 60 mg/day; P = .02). Treatment-emergent adverse events were common but mostly mild or moderate; rates were 85% (60 mg/d) and 79% (40 mg/d), similar to other SNRIs/SSRIs. Discontinuation due to adverse events was notably lower for ammoxetine (3.8% for 60 mg/d, 2.5% for 40 mg/d) compared with duloxetine (9%) and venlafaxine (12%).

Source:

He S, et al. (2025, September 2), JAMA Netw Open. Efficacy and Safety of Ammoxetine in Major Depressive Disorder: A Randomized Clinical Trial. https://pubmed.ncbi.nlm.nih.gov/40982284/