Emerging Medications for Treatment-Resistant Depression: A Review with Perspective on Mechanisms and Challenges
Brain Sciences February 6, 2025 Michael J Lucido, Boadie W Dunlop 15 citations
Non-response to initial depression treatments is common and harmful. A systematic search of US and EU clinical trial registries identified 50 trials for treatment-resistant depression, 20 for anhedonia, and 25 for suicide. Glutamate system modulation is the mechanism with the most compounds in development, including NMDA and AMPA receptor modulators. Psychedelics, especially psilocybin, have seen the greatest surge in recent years. Other mechanisms include GABA, monoamine, anti-inflammatory, and orexin modulators. Challenges for detecting efficacy include population heterogeneity, comorbid disorders, psychosocial stressors, and prior medication effects.