Daily Ammoxetine at 40, 60 mg Outperforms Placebo for MDD in Phase 2 Trial

In a recent study, ammoxetine at 40 mg and 60 mg per day demonstrated superiority over placebo in patients with major depressive disorder (MDD).1

“This randomized clinical trial demonstrates the efficacy, safety, and tolerability of ammoxetine in patients with MDD,” study investigator Shen He, MD, from the department of psychiatry at Shanghai Mental Health Center, Shanghai Jiao Tong University in China, and colleagues wrote.1

Up to 50–60% of patients are unable to tolerate first-line treatments due to adverse events.1 Ammoxetine, a novel selective serotonin and norepinephrine reuptake inhibitor, has been shown to cause fewer adverse events while providing stronger inhibition of serotonin and norepinephrine transporters.

The team conducted a phase 2 randomized clinical trial to assess the efficacy and safety of ammoxetine for adults with MDD.1 The primary outcome was the change in Montgomery-Åsberg Depression Rating Scale (MADRS) total score from baseline to 8 weeks.

This multicenter, double-masked, placebo-controlled, parallel-group, fixed-dose study included 239 patients aged 18 – 65 years (mean age, 30.4 years; 66.1% females) from 15 study centers in China. Investigators randomized participants 1:1:1 to either the ammoxetine 40 mg (n = 80), ammoxetine 60 mg (n = 80), or placebo arm (n = 79), and followed them up for 10 weeks.1

The analysis showed that both ammoxetine doses led to statistically significant improvements in MADRS total score at week 8 compared with placebo. The least-squares mean changes from baseline were -16.7 for ammoxetine 40 mg, -16.6 for ammoxetine 60 mg, and -13.5 for placebo. Compared with placebo, the differences were -3.3 (97.3% confidence interval [CI], -6.3 to -0.3) for ammoxetine 40 mg and 3.1 (97.3% CI, -6.2 to 0.0) for ammoxetine 60 mg.1

“The improvement seen with ammoxetine was comparable to that reported in studies of duloxetine, vortioxetine, and vilazodone,” investigators noted.1 “Previous trials indicated LS mean changes of 14.3 for vortioxetine 15 mg/d, 15.6 for vortioxetine 20 mg/d, 16.9 for duloxetine 60 mg/d, and 13.3 for vilazodone 40 mg/d.”

The study found consistent results in the per-protocol set analysis at week 8 for ammoxetine 40 mg and 60 mg, with mean changes of -3.2; 97.3% CI, -6.1 to -0.2 and -3.18; 97.3% CI, -6.2 to -0.2%, respectively. The findings show that ammoxetine at 40 mg or 60 mg is superior at improving the MADRS total score than placebo.1

Treatment-emergent adverse events occurred in 68 participants (85.0%) and 63 participants (78.8%) on ammoxetine 60 mg and 40 mg, respectively, compared to 48 participants (60.8%) on placebo. Most adverse events were mild to moderate in severity.1 The most reported treatment-emergent adverse events included dry mouth, nausea, and dizziness, which was similar to the reported safety profile of SSRIs and SNRIs.

Ammoxetine displayed a lower discontinuation rate (3.8% in the 60 mg arm; 2.5% in the 40 mg arm) than other antidepressant drugs. A meta-analysis on antidepressant trials reported that the average discontinuation rate due to treatment-emergent adverse events was 7%.2

Often, in serotonin reuptake inhibitors, sexual dysfunction is cited as the adverse event leading to discontinuation.1 However, no patients on ammoxetine discontinued due to sexual dysfunction.

Moreover, participants on ammoxetine also had a lower risk of liver issues, with no one discontinuing treatment due to these complications. The incidence of liver function abnormalities was 0.6% in the ammoxetine arms, which was much lower than previous reports in duloxetine trials, which found that alanine aminotransferase elevations were greater than 3 times the upper limit of normal in 1.4% of patients.1

Investigators pointed out several limitations of the study, including the small sample size, the exclusion of patients with comorbid conditions, the proof-of-concept design not allowing for a comparison between ammoxetine doses, and the absence of an active comparator arm.1

“These results support the need for further phase 3 trial investigations, which should involve larger samples,” investigators concluded.1

References

1. He S, Chen JX, Yu X, et al. Efficacy and Safety of Ammoxetine in Major Depressive Disorder: A Randomized Clinical Trial. JAMA Netw Open. 2025;8(9):e2532650. Published 2025 Sep 2. doi:10.1001/jamanetworkopen.2025.32650

2. Schalkwijk S, Undurraga J, Tondo L, Baldessarini RJ. Declining efficacy in controlled trials of antidepressants: effects of placebo dropout. Int J Neuropsychopharmacol. 2014;17(8):1343-1352. doi:10.1017/S1461145714000224