Ammoxetine: Emerging Data from a Phase 2 Antidepressant Trial

Major depressive disorder (MDD) is one of the most common mental health disorders leading to significant disability and economic burden worldwide, which will become the primary cause of disability by 2030 according to the World Health Organization.^1,2 Selective serotonin reuptake inhibitors (SSRIs) and serotonin and norepinephrine reuptake inhibitors (SNRIs) are first-line treatments with mild adverse effects.

SNRIs may outperform SSRIs because of higher efficacy, faster onset, and chronic pain alleviation, as well as fewer cardiovascular complications compared to tricyclic antidepressants and monoamine oxidase inhibitors. However, up to 50% to 60% of patients do not tolerate or respond adequately to SNRIs. Ammoxetine (Eli Lilly) is a novel SNRI derived from duloxetine, exhibiting a 3- to 10-fold greater potency than duloxetine (Cymbalta; Eli Lilly) and reduced hepatotoxicity, making it a more tolerable agent. Therefore, it was approved for efficacy and safety evaluation in a phase 2 clinical trial for patients with MDD.¹

Mechanism of Action

Ammoxetine hydrochloride is a selective dual 5-HT/NE reuptake inhibitor, targeting the 5-HT transporter (SERT) and NE transporter (NET) on the presynaptic membrane, to inhibit both 5-HT and NE reuptake into presynaptic cells. Nervous system function is enhanced as a result of increased 5-HT and NE levels in the synaptic cleft.¹

Study Design

The study was a phase 2, multicenter, double-masked, placebo-controlled, parallel-group, and fixed-dose randomized clinical trial. Patients with MDD from 15 study centers in China, aged 18 to 65 years old, were randomized into daily ammoxetine or placebo groups between March 27th, 2023, and June 13th, 2024. They were assigned in a 1:1:1 ratio by stratified blocked randomization to ammoxetine 40 mg/d, ammoxetine 60 mg/d, and placebo.¹

Patients with MDD were selected based on the Diagnostic and Statistical Manual of Mental Disorders 5th edition criteria, a Montgomery-Åsberg Depression Rating Scale (MADRS) score of 26 or higher, a Clinical Global Impressions-Severity (CGI-S) score of 4 or higher, a Hamilton Rating Scale for Depression (HAMD) score of 2 or higher, and receiving no other therapies. Patients were stratified based on baseline severity (MADRS score of 26-30 or >30, indicating moderate to severe depression, and depression diagnostic types—single and recurrent episodes). The timeline of the study is shown in Figure 1.¹

The primary end point was the mean change in MADRS score from baseline to week 8. The secondary end points included a change in baseline to week 8 in the 17-item HAMD total score, CGI-S score, CGI-Improvement score, and Hamilton Anxiety Rating Scale (HAMA) total score; a 50% decrease in MADRS and HAMD-17 scores; remission rates with MADRS (≤10) and HAMD-17 (≤7); and a 25% reduction of the MADRS score at weeks 1 and 2.¹

Clinical Trial Results

The trial (n=239) was in a per-protocol and full analysis set with 81 men and 158 women, with a mean age of 29.3 to 31.6 years old and an average body mass index of 22.7 to 23.4. Ninety percent of the enrolled patients had recurrent MDD. The trial had a mean MDD total course of 55.7 to 71.1 months, mean current MDD episode duration of 5.9 to 8.9 months, mean MADRS total score of 26 to 30, mean HAMD-17 total score of 21.8 to 22.0, mean HAMA total score of 18.8 to 19.6, and mean CGI-S total score of 4.8 to 4.9.¹ The least-squares mean change from baseline in MADRS total score is shown in figure 2.¹

There were 68 participants in the ammoxetine 60 mg/d group (85.0%), 63 participants in the ammoxetine 40 mg/d group (78.8%), and 48 participants in the placebo group (60.8%). The least-square (LS) mean change from baseline was -16.7 (1.3) for the ammoxetine 40 mg/d group, -16.6 (1.3) for the ammoxetine 60 mg/d group, and -13.5 (1.3) for the placebo group. Compared to the placebo group, in the full-analysis set, the LS mean difference was -3.3 (1.4) for the ammoxetine 40 mg/d group (97.3% CI, -6.3 to -0.3; P=0.02) and -3.1 (1.3) for the ammoxetine 60 mg/d group (97.3% CI, -6.2 to 0.0; P=0.02). Ammoxetine in the per-protocol set achieved significant results, with an LS mean difference of -3.2 (1.4) for the ammoxetine group (97.3% CI, -6.2 to -0.2; P=0.02) and -3.2 (1.4) for the ammoxetine 60 mg/d group (97.3% CI, -6.2 to - 0.2; P=0.02).¹

The secondary end points were HAMA score change from baseline to week 8. HAMA scores for the ammoxetine 40 mg/d group were higher than the change in the placebo group, with an LS mean difference of -1.8 (0.9; 95% CI, -3.4 to -0.1; P=0.04) indicating decreased anxiety. No significant differences were recorded among the ammoxetine 40 mg/d group, the ammoxetine 60 mg/d group, or the placebo group based on HAMD-17, CGI-S, CGI-I, MADRS response and remission rates, and the patients’ proportion of MADRS 25% or more score reduction at week 1 and week 2.¹

Safety Profile

This trial reported treatment-emergent adverse events as mild or moderate. Most common treatment-emergent adverse events included dry mouth, nausea, and dizziness.¹

Clinical Implications

This trial’s findings demonstrated that both ammoxetine 40 mg/d and 60 mg/d had superiority over the placebo in patients with MDD. All doses of ammoxetine were generally effective, safe, and tolerated in patients with MDD. The study was clinically significant, and the results support the need for a phase 3 clinical trial with a larger population size. Limitations were the relatively small sample size and inability to meet power (high false negative risk), limited generalizability due to the exclusion of MDD secondary to comorbid conditions, and the exclusion of first-line treatment of cognitive behavioral therapy.⁴ In addition, studies have shown most antidepressants exhibit full effects after 8 to 12 weeks, whereas this clinical trial only lasted for 8 weeks, which may not have allowed the full effect to take place.⁵

A phase 3 trial is currently underway with sertraline as an active comparator to determine the optimal dose that balances the efficacy and safety of ammoxetine.⁶

REFERENCES

1. He S, Chen JX, Yu XQ, et al. Efficacy and safety of ammoxetine in major depressive disorder. JAMA Netw Open. 2025;8(9):e2532650

2. Uyar A, Gonul AS. New and emerging pharmacologic treatment for MDD. Front Psychiatry. 2025;16. doi:10.3389/fpsyt.2025.1621887

3. Zhu X, Li Y, Luo H, Zhang Y, Zhang Z, Li J. In vitro, in vivo, and in silico approaches for evaluating the preclinical DMPK profiles of ammoxetine, a novel chiral serotonin and norepinephrine reuptake inhibitor. Front Pharmacol. 2024;15. doi:10.3389/fphar.2024.1486856

4. Gautam M, Tripathi A, Deshmukh D, Manisha G. Cognitive behavioral therapy for depression. Ind J Psychiatr. 2020;62(Suppl_2):223-229. doi:10.4103/psychiatry.IndianJPsychiatry_772_19

5. Ward W, Haslam A, Prasad V. Antidepressant trial duration versus duration of real-world use: a systematic analysis. Am J Med. 2025;138(10):1400-1407. doi:10.1016/j.amjmed.2025.04.037

6. The research of ammoxetine hydrochloride enteric-coated tablets in subjects with depression. ClinicalTrials.gov identifier: NCT06827431. Updated February 14, 2025. Accessed June 22, 2026. https://clinicaltrials.gov/study/NCT06827431?intr=ammoxetine%20%20sertraline&cond=depression&rank=1