Neurophysiological evidence that frontoparietal connectivity and GABA-A receptor changes underpin the antidepressant response to ketamine.
Rachael Sumner, Rebecca McMillan, Anna Forsyth, Suresh Muthukumaraswamy, Alexander D Shaw
Translational Psychiatry February 24, 2024 DOI: 10.1038/s41398-024-02738-w (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Observational cohort Peer reviewed |
|---|---|
| Sample size | 30 |
| Population | Patients with major depressive disorder (MDD) |
| Intervention | Ketamine |
| Dose | 0.44 mg/kg comprising a bolus and infusion |
| Topics | Esketamine Ketamine |
| Keywords | Depression treatment Ketamine therapy Brain connectivity Psychopharmacology |
| Citations | 7 |
| Key findings | Ketamine infusion increased parietal-to-frontal AMPA-mediated connectivity and decreased the frontal GABA time constant, both correlated with antidepressant response, while NMDA receptor changes were not significant. |
Abstract
Revealing the acute cortical pharmacodynamics of an antidepressant dose of ketamine in humans with depression is key to determining the specific mechanism(s) of action for alleviating symptoms. While the downstream effects are characterised by increases in plasticity and reductions in depressive symptoms-it is the acute response in the brain that triggers this cascade of events. Computational modelling of cortical interlaminar and cortico-cortical connectivity and receptor dynamics provide the opportunity to interrogate this question using human electroencephalography (EEG) data recorded during a ketamine infusion. Here, resting-state EEG was recorded in a group of 30 patients with major depressive disorder (MDD) at baseline and during a 0.44 mg/kg ketamine dose comprising a bolus and infusion. Fronto-parietal connectivity was assessed using dynamic causal modelling to fit a thalamocortical model to hierarchically connected nodes in the medial prefrontal cortex and superior parietal lobule. We found a significant increase in parietal-to-frontal AMPA-mediated connectivity and a significant decrease in the frontal GABA time constant. Both parameter changes were correlated across participants with the antidepressant response to ketamine. Changes to the NMDA receptor time constant and inhibitory intraneuronal input into superficial pyramidal cells did not survive correction for multiple comparisons and were not correlated with the antidepressant response. These results provide evidence that the antidepressant effects of ketamine may be mediated by acute fronto-parietal connectivity and GABA receptor dynamics. Furthermore, it supports the large body of literature suggesting the acute mechanism underlying ketamine's antidepressant properties is related to GABA-A and AMPA receptors rather than NMDA receptor antagonism.
Comparable studies
Other observational and cohort studies on ketamine, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Taming the Ketamine Tiger Volunteers from a prison population | 2010 | Observational study | n = 20 |
| Increased spontaneous MEG signal diversity for psychoactive doses of ketamine, LSD and psilocybin Humans | 2017 | Observational study | |
| Disruption of Frontal–Parietal Communication by Ketamine, Propofol, and Sevoflurane Surgical patients undergoing induction of anesthesia with intravenous ketamine | 2013 | Observational cohort | n = 30 |
| Do the dissociative side effects of ketamine mediate its antidepressant effects? Treatment-resistant inpatients with major depressive disorder or bipolar disorder | 2014 | Observational cohort | n = 108 |
| Concomitant BDNF and sleep slow wave changes indicate ketamine-induced plasticity in major depressive disorder Patients with treatment-resistant major depressive disorder | 2012 | Observational cohort | n = 30 |
Citations in the library
Cited by 4
- Correlations between major depressive disorder, splenic morphology, and immune function. BMC Psychiatry May 12, 2025
- Modulatory effects of ketamine on EEG source-based resting state connectivity in treatment resistant depression. Translational Psychiatry March 6, 2026
- Hope for Neurotic Disorders: A Summary of New Zealand Research on the Development of Biomarkers and Novel Treatments. Journal of the Royal Society of New Zealand February 1, 2026
- Ketamine in severe, highly treatment-resistant depression—a retrospective case study and a perspective June 7, 2024
Cites 14
- Synaptic Dysfunction in Depression: Potential Therapeutic Targets Science October 4, 2012
- Mechanisms of Ketamine Action as an Antidepressant Molecular Psychiatry March 13, 2018
- Disruption of Frontal–Parietal Communication by Ketamine, Propofol, and Sevoflurane Anesthesiology May 22, 2013
- Antidepressants Normalize the Default Mode Network in Patients With Dysthymia JAMA Psychiatry February 6, 2013
- Evidence that Subanesthetic Doses of Ketamine Cause Sustained Disruptions of NMDA and AMPA-Mediated Frontoparietal Connectivity in Humans Journal of Neuroscience August 19, 2015
and 9 more in the library