Novel NMDA Receptor Antagonist Wins for Major Depression

An investigational N-methyl-D-aspartate (NMDA)-receptor antagonist was effective at treating major depressive disorder in the phase III GEMINI trial.

The 1:1 randomized controlled study of 327 adults with major depression found that twice-daily, oral treatment with the dextromethorphan-bupropion tablet (AXS-05) resulted in a significant reduction in total Montgomery-Åsberg Depression Rating Scale (MADRS) score versus placebo, reported Cedric O'Gorman, MD, MBA, of Axsome Therapeutics in New York City, and colleagues.

Specifically, patients on treatment saw an average 16.6-point reduction in MADRS score from baseline versus an 11.9-point reduction for placebo (P=0.002) -- meeting the trial's primary endpoint -- the group reported at the American Psychiatric Association (APA) virtual meeting.

Patients on AXS-05 also saw a significant improvement in depression rating within the first week of treatment (-7.3 vs -4.9 for placebo, P=0.007) -- meeting the trial's key secondary endpoint -- and were maintained throughout the 6-week trial.

By week 6, 54% of patients on active treatment were considered responsive to treatment, defined as a 50% or greater improvement in MADRS score, versus only 34% on placebo (P<0.001). Also at this time point, 40% of patients on treatment achieved clinical remission of their major depression versus 17% on placebo (P<0.001).

Symptom improvement, measured by Clinician-reported Global Improvement (CGI-I) score, was also seen, marked by a 1.7-point change from baseline for those on treatment versus a 1.2-point improvement for those on placebo by week 6 (P=0.002).

Quality of life and functional improvement was also achieved by the end of the trial, as measured by the Quality of Life Enjoyment and Satisfaction Questionnaire-Short Form (Q-LES-Q-SF) score and Sheehan Disability Scale (SDS) total score changes from baseline:

• Q-LES-Q-SF score: 19.8 versus 14.4 for placebo (P=0.011)

• SDS score: 9.0 versus 6.3 for placebo (P=0.002)

The novel agent is made up of 45 mg of dextromethorphan -- used most commonly as a cough suppressant -- acting as the antagonist of the NMDA receptor, as well as an ionotropic glutamate receptor and a sigma-1 receptor agonist.

This is combined with 105 mg of bupropion (Wellbutrin), a norepinephrine and dopamine reuptake inhibitor that bolsters the bioavailability of dextromethorphan.

The agent received Breakthrough Therapy designation from the FDA in March 2019 for the treatment of major depressive disorder. In April 2021, the agency granted priority review to Axsome Therapeutics' new drug application, setting a Prescription Drug User Fee Act action goal date of August 22, 2021.

"Currently approved oral antidepressants act primarily via monoaminergic mechanisms and are associated with prolonged time to clinically meaningful response (up to 6-8 weeks) and adverse events that can impact adherence to treatment," the researchers pointed out on their poster, adding that there's "an urgent need for mechanistically-novel, effective, well-tolerated and rapidly-acting antidepressants that can provide sustained clinical benefit."

The U.S.-based multicenter trial included adults ages 18 to 65 with the DSM-5 criteria for moderate to severe major depressive disorder with baseline MADRS total scores of 25 or higher and baseline CGI-S scores of 4 or higher. The majority of the cohort were female with an average age of 42, more than half were white and over a third were Black, and average baseline MADRS and CGI-S scores were 33 and 4.6, respectively.

Some exclusion criteria included history of schizophrenia, bipolar disorder, or obsessive compulsive disorder, as well as having electroconvulsive therapy, vagus nerve stimulation, transcranial magnetic stimulation, or other central nervous system treatment within the past 6 months.

Treatment was also well tolerated, as only 6.2% of those on AXS-05 discontinued due to adverse events, the most common of which were dizziness (16%), nausea (13%), headache (8%), diarrhea (6.8%), somnolence (6.8%), and dry mouth (5.6%).

The treatment wasn't linked to any psychomimetic effects, increased sexual dysfunction, or weight gain, the researchers pointed out.

In the related phase III COMET study, also reported at the APA meeting, O'Gorman and colleagues enrolled a total of 876 individuals: those who participated in the GEMINI trial plus new participants.

The 12-month extension study confirmed the long-term efficacy of AXS-05, with those on treatment having a 23-point average improvement in baseline MADRS total score by month 12. After a year of treatment, 83% of participants were considered responders to treatment and 69% achieved clinical remission, the researchers reported.

They added that during this study extension, there were no additional safety signals that arose related to treatment, and the rates of discontinuation due to adverse events remained low (8.4%).