Highlight
– Ammoxetine, a novel selective serotonin-norepinephrine reuptake inhibitor (SNRI), was evaluated in a multicenter, placebo-controlled phase 2 trial in adults with major depressive disorder (MDD).
– Both 40 mg/d and 60 mg/d doses significantly reduced depressive symptoms compared with placebo over 8 weeks.
– The safety profile was generally favorable, with mostly mild to moderate adverse events.
– Ammoxetine offers potential advantages over existing antidepressants by reducing hepatotoxicity and improving tolerability.
Study Background and Disease Burden
Major depressive disorder (MDD) is a prevalent and disabling mental health condition globally, contributing to significant morbidity, mortality, and socioeconomic costs. Despite advances in therapeutics, up to 50% to 60% of MDD patients either do not respond adequately or cannot tolerate currently available first-line antidepressants. Commonly used selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) can have adverse effects, including gastrointestinal symptoms, sexual dysfunction, and hepatotoxicity, which limit adherence and overall treatment success.
Ammoxetine is a novel SNRI with higher potency for serotonin and norepinephrine transport inhibition while exhibiting a reduced risk of adverse effects and hepatotoxicity demonstrated in preclinical studies. This profile positions ammoxetine as a promising candidate to fill an unmet need for more effective and better-tolerated antidepressant options. The present phase 2 randomized clinical trial assesses the efficacy and safety of two fixed doses of ammoxetine in adults with MDD.
Study Design
This multicenter, double-masked, placebo-controlled, parallel-group, fixed-dose phase 2 trial was conducted at 15 centers across China. Eligible participants were adults aged 18 to 65 years with a diagnosis of MDD. From March 27, 2023, to June 13, 2024, 239 patients were randomized equally (1:1:1) to receive either ammoxetine 40 mg/day, ammoxetine 60 mg/day, or placebo once daily for 8 weeks, with follow-up continuing to 10 weeks.
The primary efficacy endpoint was the change in Montgomery-Åsberg Depression Rating Scale (MADRS) total score from baseline to week 8. Efficacy analyses were conducted on both the full-analysis and per-protocol populations using least-squares (LS) mean differences. Safety assessments included treatment-emergent adverse events (TEAEs) and laboratory parameters summarized descriptively.
Key Findings
The study enrolled 239 patients (mean age 30.4 years, 66.1% female). Baseline demographics and disease severity were balanced across groups. Of these, 80 patients received ammoxetine 60 mg/d, 80 received ammoxetine 40 mg/d, and 79 received placebo.
At week 8, patients treated with ammoxetine demonstrated significant reductions in MADRS scores compared to placebo. The LS mean changes from baseline were -16.7 (SE 1.3) for the 40 mg group, -16.6 (SE 1.3) for the 60 mg group, and -13.5 (SE 1.3) for placebo. The difference versus placebo was -3.3 (97.3% CI, -6.3 to -0.3) for the 40 mg/d dose and -3.1 (97.3% CI, -6.2 to 0.0) for the 60 mg/d dose, meeting pre-specified statistical significance thresholds in the full-analysis set.
The per-protocol analysis corroborated these findings, with LS mean differences versus placebo of -3.2 (97.3% CI, -6.2 to -0.2) for the 40 mg/d group and -3.18 (97.3% CI, -6.2 to -0.2) for the 60 mg/d group. These consistent results support the robustness of efficacy outcomes.
In terms of safety, treatment-emergent adverse events (TEAEs) occurred in 85.0% of patients in the 60 mg/d group, 78.8% in the 40 mg/d group, and 60.8% in placebo. The majority of TEAEs were mild or moderate, with no new safety signals detected. Common adverse events included insomnia, nausea, and headache. Importantly, no significant hepatotoxicity was reported, distinguishing ammoxetine from some currently available antidepressants.
Expert Commentary
This phase 2 trial provides encouraging evidence that ammoxetine is an effective antidepressant with a favorable tolerability profile in adults with MDD. The statistically significant improvements in MADRS scores with both 40 mg and 60 mg doses, along with consistent per-protocol analyses, underscore its potential clinical utility.
The reduction of adverse effects, especially hepatotoxicity, is particularly noteworthy given the chronic nature of MDD therapy and limitations of existing agents. The comparable efficacy between doses suggests clinicians may individualize treatment based on patient tolerability and preferences.
However, there are limitations inherent to phase 2 trials. The relatively short duration of 8 weeks limits long-term efficacy and safety insights. The trial population, aged 18-65 and enrolled exclusively in China, may limit generalizability. Future phase 3 trials with larger, diverse populations and longer follow-up are essential to validate these findings and assess real-world effectiveness.
Conclusion
The randomized controlled trial assessing ammoxetine for MDD demonstrated significant efficacy over placebo for both 40 mg/d and 60 mg/d doses with a well-tolerated safety profile. Ammoxetine may represent a promising new therapeutic option for patients with MDD, particularly those who do not tolerate or respond to current treatments. Pending larger confirmatory trials, ammoxetine has the potential to fill an important treatment gap in the management of this burdensome disorder.
References
He S, Chen JX, Yu X, Lin H, Wang Z, Li X, Zhou Y, Liu YS, Zhang H, Wang J, An C, Liu H, Li C, Ni S, Li H. Efficacy and Safety of Ammoxetine in Major Depressive Disorder: A Randomized Clinical Trial. JAMA Netw Open. 2025 Sep 2;8(9):e2532650. doi: 10.1001/jamanetworkopen.2025.32650. PMID: 40982284.