Rapid-Acting Antidepressants: Targeting Neuroplasticity Beyond Monoamines.
Saumya Das, Avijit Mazumder, Deepanshi Rana
Central nervous system agents in medicinal chemistry November 3, 2026 DOI: 10.2174/0118715249485751261025102238 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Review Peer reviewed |
|---|---|
| Topics | Depression Ketamine Neuroplasticity |
| Keywords | Ampa potentiators Bdnf-trkb signaling Neuroplasticity models Neurosteroids Psychedelics Rapid-acting antidepressants |
| Key findings | The review describes ketamine as producing rapid antidepressant effects in treatment-resistant depression, acting within hours through glutamate release, AMPA receptor activation, BDNF-TrkB signaling, and mTOR engagement that drive synaptic remodeling. It frames ketamine as an adjunct or alternative to monoaminergic antidepressants and compares it with psychedelics, neurosteroids, and investigational NMDA modulators, while noting translational limitations, biomarker feasibility concerns, and ethical challenges in digital therapeutics. |
Abstract
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.