Rapid-Acting Glutamatergic Therapy in MDD: Mechanism and Trial Data

In "Rapid-Acting Glutamatergic Therapy in MDD: Mechanism and Trial Data," the panel explores what changes when a glutamatergic mechanism arrives in an oral tablet.

Dr. Alva introduces dextromethorphan-bupropion as a rapid glutamatergic mechanism without the baggage that has followed ketamine. He asks Dr. Shirikjian to walk through the actual numbers from the phase 2 and phase 3 program rather than the label.

Dr. Shirikjian describes trials comparing placebo plus an antidepressant against the combination, with change in MADRS as the primary endpoint over roughly five weeks. The trials looked at remission and at 50% or greater improvement, but the central question was how quickly symptoms improved. She frames the clinical stakes directly. Established antidepressants, including SSRIs, take six to eight to ten weeks or longer, and the goal is getting patients better sooner. When a patient is suicidal, bringing that down quickly matters enormously. In the short-term trials, separation appeared as early as week one and was sustained through the end of the trial, and the long-term studies reproduced similar data. She flags that the side effect profile differs, with dizziness at the top of the list where clinicians are not used to seeing it. Weight gain did not emerge as significant, which matters because her patients ask for that and the list of options is short. She notes that in the phase 2 trial the comparator was bupropion alone, and the combination surpassed it, which challenges the assumption that bupropion does the heavy lifting.

Dr. Shirikjian then explains the mechanism she says she had to unlearn. She initially assumed bupropion was the antidepressant and dextromethorphan merely a booster. In fact bupropion acts as a CYP2D6 inhibitor, slowing metabolism so dextromethorphan's half-life extends from roughly eight hours to roughly 22. Dextromethorphan is the star of the show, working as both friend and foe at NMDA and sigma-1. She clarifies that she misspoke, and that the agent was studied as monotherapy against placebo.

The next episode in this series, "Two New MDD Approvals: 5-HT1A Agonism and Adjunctive Atypical Antipsychotics," features Dr. Clayton on two approvals that many colleagues do not yet know exist.