The novel serotonin norepinephrine reuptake inhibitor (SNRI) ammoxetine may effectively treat major depressive disorder (MDD) while avoiding some side effects common to other antidepressants, new phase 2 data suggested.

Investigators found that participants receiving ammoxetine at either 40 mg/d or 60 mg/d experienced notable improvements in depressive symptoms compared with placebo, with most side effects reported as mild to moderate.

“These findings support the safety and efficacy of ammoxetine in the treatment of MDD, providing a basis for phase 3 validation,” the investigators led by Shen He, MD, of the Department of Psychiatry at Shanghai Mental Health Center and the Shanghai Jiao Tong University School of Medicine in Shanghai, China, wrote.

The study was published online on September 22 in JAMA Network Open.

New Treatment Options Needed

While selective serotonin reuptake inhibitors (SSRIs) and SNRIs are first-line options for MDD, about 50%-60% of patients do not respond to treatment, the researchers noted.

SNRIs have the potential to act more rapidly than SSRIs and avoid the drawbacks of older treatments, such as tricyclic antidepressants and monoamine oxidase inhibitors, which carry cardiovascular risks.

Despite this, the SNRI duloxetine appears to carry a higher risk for hepatotoxicity than other SNRIs, such as venlafaxine. However, ammoxetine, a derivative of duloxetine, seems to reduce some of these liver-related risks, researchers noted.

“[C]onsidering the burden of MDD and the potential of SNRIs, there is a need for new compounds within this class,” the researchers noted.

To evaluate the safety and efficacy of ammoxetine in treating adults with MDD, researchers conducted the phase 2 randomized clinical trial. It included 239 patients with MDD who received treatment with 40 mg of ammoxetine, 60 mg of ammoxetine, or placebo once per day for 8 weeks. Patients had a mean age of 30.4 years, and 66.1% were women.

Lower Hepatotoxicity Risk

The primary outcome was change in Montgomery-Åsberg Depression Rating Scale (MADRS) total score at 8 weeks compared with baseline. They also conducted efficacy and safety analyses for all three study groups.

Results showed significant improvements in MADRS scores among patients receiving ammoxetine in the full analysis set, with least squares mean changes from baseline of -3.3 (97.3% CI, -6.3 to -0.3; P = .02) in the 40-mg group and -3.1 (97.3% CI, -6.2 to 0.0; P = .02) in the 60-mg group compared with placebo. These differences remained significant in the per-protocol set of 221 patients (P = .02 for both).

Adverse events were more common among participants receiving ammoxetine than placebo, occurring in 85.0% of those on 60 mg/d, 78.8% on 40 mg/d, and 60.8% on placebo. Most adverse events were mild-to-moderate in severity. No serious adverse events occurred in the 40-mg group and placebo group, while one patient reported a moderate adverse event in the 60-mg group.

Liver function abnormalities occurred in 0.6% of patients in both ammoxetine groups, but no participants discontinued treatment due to these abnormalities, researchers reported.

The investigators noted that prior research on duloxetine found 1.4% of patients experienced alanine aminotransferase elevations above three times the normal limit, with 0.3% stopping treatment because of liver enzyme increases.

“These findings suggest that ammoxetine has a lower risk of liver safety issues compared with duloxetine,” they wrote.

“Overall, the data indicate that ammoxetine demonstrates a comparable or potentially superior safety and tolerability profile relative to commonly used antidepressants,” he and colleagues added.

The findings of the study “support the need for further phase 3 trial investigations, which should involve larger samples,” the investigators concluded.

This study was supported by CSPC Zhongqi Pharmaceutical Technology Shijiazhuang Co., Ltd. The authors reported having no relevant conflicts of interest.