The anterior cingulate cortex as a key locus of ketamine’s antidepressant action
Laith Alexander, Luke A. Jelen, Mitul A. Mehta, Allan H. Young
Neuroscience & Biobehavioral Reviews May 10, 2021 DOI: 10.1016/j.neubiorev.2021.05.003 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Review Peer reviewed |
|---|---|
| Intervention | Ketamine |
| Topics | Ketamine Esketamine |
| Keywords | Antidepressant Anterior cingulate cortex Cognition Hippocampus Central nervous system |
| Citations | 79 |
| Key findings | Changes in anterior cingulate cortex activity are critically important in mediating the antidepressant effects of ketamine. |
Abstract
The subdivisions of the anterior cingulate cortex (ACC) - including subgenual, perigenual and dorsal zones - are implicated in the etiology, pathogenesis and treatment of major depression. We review an emerging body of evidence which suggests that changes in ACC activity are critically important in mediating the antidepressant effects of ketamine, the prototypical member of an emerging class of rapidly acting antidepressants. Infusions of ketamine induce acute (over minutes) and post-acute (over hours to days) modulations in subgenual and perigenual activity, and importantly, these changes can correlate with antidepressant efficacy. The subgenual and dorsal zones of the ACC have been specifically implicated in ketamine's anti-anhedonic effects. We emphasize the synergistic relationship between neuroimaging studies in humans and brain manipulations in animals to understand the causal relationship between changes in brain activity and therapeutic efficacy. We conclude with circuit-based perspectives on ketamine's action: first, related to ACC function in a central network mediating affective pain, and second, related to its role as the anterior node of the default mode network.
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 29
- Antidepressant and anxiolytic effects of activating 5HT2A receptors in the anterior cingulate cortex and the theoretical mechanisms underlying them - A scoping review of available literature. Brain Research 2025
- A unified model of ketamine's dissociative and psychedelic properties. Journal of Psychopharmacology December 17, 2022
- Neuroimaging-Derived Biomarkers of the Antidepressant Effects of Ketamine Biological Psychiatry: Cognitive Neuroscience and Neuroimaging November 25, 2022
- Preliminary evidence that ketamine alters anterior cingulate resting-state functional connectivity in depressed individuals Translational Psychiatry December 3, 2023
- Predicting Antidepressant Effects of Ketamine: the Role of the Pregenual Anterior Cingulate Cortex as a Multimodal Neuroimaging Biomarker The International Journal of Neuropsychopharmacology August 10, 2022
and 24 more in the library
Cites 46
- A default mode of brain function Proceedings of the National Academy of Sciences January 16, 2001
- mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Science August 19, 2010
- Activation of Glutamatergic Neurotransmission by Ketamine: A Novel Step in the Pathway from NMDA Receptor Blockade to Dopaminergic and Cognitive Disruptions Associated with the Prefrontal Cortex Journal of Neuroscience April 15, 1997
- NMDAR inhibition-independent antidepressant actions of ketamine metabolites Nature April 24, 2016
- Efficacy and Safety of Intranasal Esketamine Adjunctive to Oral Antidepressant Therapy in Treatment-Resistant Depression JAMA Psychiatry December 27, 2017
and 41 more in the library