The hippocampus as a central hub in ketamine's antidepressant action: from molecules to circuit rewiring.
Dongsun Park, Gwangho Lee, Bokyum Kim, Minjoo Seong, Ji-Woon Kim
Neuropsychopharmacology February 1, 2026 DOI: 10.1038/s41386-025-02288-9 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Review Peer reviewed |
|---|---|
| Topics | Esketamine Ketamine |
| Citations | 1 |
| Key findings | Ketamine's rapid and sustained antidepressant effects are mediated through hippocampal synaptic plasticity, which operates independently of HPA axis normalization. |
Abstract
Ketamine has emerged as a rapid-acting antidepressant that challenges classical monoaminergic frameworks and highlights the importance of synaptic and circuit-level plasticity in mood regulation. This review examines the hippocampus as a key site through which ketamine exerts both rapid and sustained antidepressant effects. We synthesize evidence showing that ketamine enhances hippocampal synaptic plasticity via mechanisms including NMDAR blockade of spontaneous neurotransmission, BDNF-TrkB signaling, MeCP2-dependent transcriptional priming, and adult neurogenesis. Molecular modulators such as Reelin, which influence NMDAR signaling and synaptic function, may also shape the efficacy of ketamine in a subset of individuals. Importantly, these hippocampal effects occur in coordination with broader network interactions, particularly with the medial prefrontal cortex and lateral habenula, allowing for circuit-level integration of antidepressant responses. Notably, ketamine's therapeutic actions are dissociable from normalization of hypothalamic-pituitary-adrenal (HPA) axis function, underscoring a shift away from neuroendocrine-based models. By integrating molecular, synaptic, and systems-level findings, this review provides a hippocampus-centered framework for understanding ketamine's antidepressant mechanisms and outlines novel strategies for circuit-informed, fast-acting antidepressant development.
Comparable studies
Other narrative reviews on ketamine, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Ketamine and Ketamine Metabolite Pharmacology: Insights into Therapeutic Mechanisms | 2018 | Review | |
| Mechanisms of Ketamine Action as an Antidepressant | 2018 | Review | |
| Synthesizing the Evidence for Ketamine and Esketamine in Treatment-Resistant Depression: An International Expert Opinion on the Available Evidence and Implementation Adults with treatment-resistant depression | 2021 | Review | |
| Ketamine Pharmacology: An Update (Pharmacodynamics and Molecular Aspects, Recent Findings) | 2013 | Review | |
| A Consensus Statement on the Use of Ketamine in the Treatment of Mood Disorders | 2017 | Review and consensus statement |
Citations in the library
Cited by 3
- Integrating multi-receptor and neuron–glia mechanisms of ketamine's antidepressant action: a convergence framework for understanding efficacy Frontiers in Molecular Neuroscience October 21, 2026
- Network dysregulation in depression: A synthesis of HPA Axis, BDNF signaling, and neurotransmitter interactions across multidimensional systems. Pharmacology, Biochemistry, and Behavior August 1, 2026
- Investigation of Potential Therapeutic Effects of New Rapid-Acting Antidepressant Drugs (RAADs) Using Stress-Based Models of Depression Biomolecules August 24, 2026
Cites 39
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- mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Science August 19, 2010
- Synthesizing the Evidence for Ketamine and Esketamine in Treatment-Resistant Depression: An International Expert Opinion on the Available Evidence and Implementation American Journal of Psychiatry March 17, 2021
- Side-effects associated with ketamine use in depression: a systematic review. The Lancet Psychiatry 2018
- BDNF Release Is Required for the Behavioral Actions of Ketamine The International Journal of Neuropsychopharmacology October 31, 2014
and 34 more in the library