Neurophysiological evidence that frontoparietal connectivity and GABA-A receptor changes underpin the antidepressant response to ketamine

• Published in: Translational psychiatry Vol. 14; no. 1; p. 116
• Main Authors: Sumner, Rachael L., McMillan, Rebecca L., Forsyth, Anna, Muthukumaraswamy, Suresh D., Shaw, Alexander D.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 24-02-2024; Nature Publishing Group
• Subjects: 631/378; 692/699/476/1414; Antidepressants; Antidepressive Agents - pharmacology; Antidepressive Agents - therapeutic use; Behavioral Sciences; Biological Psychology; Depressive Disorder, Major - drug therapy; gamma-Aminobutyric Acid; Humans; Ketamine; Ketamine - pharmacology; Ketamine - therapeutic use; Medicine; Medicine & Public Health; Neurosciences; Pharmacotherapy; Psychiatry; Receptors, GABA-A; Receptors, N-Methyl-D-Aspartate
• ISSN: 2158-3188; 2158-3188
• DOI: 10.1038/s41398-024-02738-w

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.