Nine antidepressant compounds with mechanisms beyond the monoaminergic hypothesis have shown positive results in phase II or III trials. AXS-05 (dextromethorphan and bupropion) and ansofaxine hydrochloride outperformed placebo in phase III trials for major depressive disorder or treatment-resistant depression. MIJ821, nitrous oxide, psilocybin, ayahuasca, botulinum toxin A facial injection, prasterone, and casopitant each showed at least one positive phase II result. Ayahuasca produced a greater response rate than placebo at one week, suggesting rapid antidepressant effects. These novel compounds may expand treatment options if preliminary findings are confirmed.
In an open-label study of 30 patients with treatment-resistant depression, four intravenous ketamine infusions (0.5 mg/kg) over two weeks rapidly reduced depression severity: the average Montgomery-Åsberg Depression Rating Scale score fell from 30.6 to 20.3 after the fourth infusion, and 26.7% of participants achieved remission. However, only 13.3% remained in remission at 12 months. Early changes in the metabolite 3-hydroxybutyrate predicted the degree of improvement both after the fourth infusion and at 12 months, suggesting it could serve as a biomarker for treatment response. The findings point toward more individualized use of ketamine infusions.