Ketamine and Evolving Neuroplasticity.
Angel Prabakar
Clinical drug investigation June 13, 2026 DOI: 10.1007/s40261-026-01565-9 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Review Peer reviewed |
|---|---|
| Topics | Esketamine Ketamine Neuroplasticity |
| Key findings | Ketamine's rapid antidepressant effects are driven by a cascade of neuroplastic changes over hours to days, linking preclinical molecular mechanisms to clinical recovery. |
Abstract
Ketamine has revolutionized the treatment of mood disorders by offering rapid antidepressant effects, particularly in individuals with treatment-resistant depression. Unlike traditional monoaminergic antidepressants, ketamine acts primarily through antagonism of the N-methyl-D-aspartate (NMDA) receptor, initiating a cascade of glutamatergic signaling that promotes synaptic plasticity, neurogenesis, and rapid symptom relief. However, while its mechanisms are increasingly understood, the temporal trajectory of these neuroplastic changes-and their behavioral correlates-remain poorly defined. This review synthesizes both preclinical and clinical evidence on the time-dependent effects of ketamine across molecular, cellular, and behavioral domains. Preclinical studies are examined to characterize rapid molecular and synaptic changes, including brain-derived neurotrophic factor (BDNF) signaling, activation of the mechanistic target of rapamycin (mTOR) pathway, and modulation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, which collectively drive early phases of synaptic remodeling. In parallel, clinical studies are reviewed to evaluate how these biological processes correspond to changes in mood, motivation, cognition, and functional outcomes in patients, with particular emphasis on the timing of antidepressant response and durability of effects. Special attention is given to how ketamine-induced neuroplasticity unfolds over hours to days, and how this temporal progression links mechanistic findings from preclinical models with observed clinical recovery. By framing ketamine's action within a plasticity-centered model of antidepressant response, this review provides a novel perspective that integrates neuroscience and clinical psychiatry. It also identifies critical gaps in translational research and offers a roadmap for optimizing the therapeutic use of ketamine and future fast-acting antidepressants.
Comparable studies
Other narrative reviews on neuroplasticity, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| A neurotrophic hypothesis of depression: role of synaptogenesis in the actions of NMDA receptor antagonists | 2012 | Review | |
| Towards an understanding of psychedelic-induced neuroplasticity. Review of preclinical and clinical studies | 2023 | Review | |
| Buddha's Brain: Neuroplasticity and Meditation [In the Spotlight] | 2008 | Review | |
| Neuroplasticity as a convergent mechanism of ketamine and classical psychedelics | 2021 | Review | |
| Psychedelics in Psychiatry: Neuroplastic, Immunomodulatory, and Neurotransmitter Mechanisms | 2020 | Review |
Citations in the library
Cites 28
- Mechanisms of Ketamine Action as an Antidepressant Molecular Psychiatry March 13, 2018
- Attenuation of Antidepressant Effects of Ketamine by Opioid Receptor Antagonism American Journal of Psychiatry August 29, 2018
- Ketamine: 50 Years of Modulating the Mind Frontiers in Human Neuroscience November 29, 2016
- GABA interneurons are the cellular trigger for ketamine's rapid antidepressant actions. Journal of Clinical Investigation November 19, 2019
- Ketamine and rapid antidepressant action: new treatments and novel synaptic signaling mechanisms Neuropsychopharmacology July 24, 2023
and 23 more in the library