Rapid-Acting Antidepressants: Targeting Neuroplasticity Beyond Monoamines

Depression remains a leading cause of morbidity worldwide, with conventional monoaminergic antidepressants such as SSRIs and SNRIs limited by delayed onset and high rates of treatment resistance. Novel approaches that modulate neuroplasticity, particularly NMDA receptor antagonists like ketamine, have demonstrated rapid efficacy in treatment-resistant depression. Ketamine relieves symptoms within hours by promoting glutamate release, AMPA receptor activation, BDNF-TrkB signaling, and mTOR pathway engagement, leading to synaptic remodeling. This review focuses on ketamine as an adjunct or alternative to monoaminergic therapies, highlighting mechanistic pathways of synaptic scaling and dendritic spine formation. Comparative insights into psychedelics, neurosteroids, and investigational NMDA modulators are also discussed, with emphasis on translational limitations, biomarker feasibility, and ethical challenges in digital therapeutics.