After decades of limited progress in treating major depressive disorder (MDD), especially for patients unresponsive to standard antidepressants, the serendipitous discovery of ketamine's antidepressant effects has renewed optimism. This has spurred development of related drugs like S-ketamine and oral NMDA antagonists showing promise in late-stage trials. An extended-release combination of bupropion (105 mg) and dextromethorphan (45 mg) reduced MADRS total scores in recipients. Neurosteroids such as brexanolone and zuranolone represent another class, modulating GABA neurotransmission, a pathway long used for insomnia and anxiety. Psychedelic drugs, after nearly 50 years of legal restrictions, are also being investigated, with psilocybin under study for treatment-resistant depression.
A single day of treatment with an inhaled synthetic formulation of mebufotenin (GH001) significantly reduced depression symptoms in adults with treatment-resistant depression compared to placebo. In a randomized, double-blind trial of 81 patients, those receiving up to three escalating doses of GH001 showed an average 15.5-point greater improvement on the Montgomery-Åsberg Depression Rating Scale by day 8 than those on placebo. Remission rates were 57.5% for GH001 and 0% for placebo. No severe or serious adverse events occurred. The findings suggest GH001 may be a rapid-acting, well-tolerated treatment option for treatment-resistant depression.