Association of the delayed changes in glutamate levels and functional connectivity with the immediate network effects of S-ketamine

• Published in: Translational psychiatry Vol. 13; no. 1; p. 60
• Main Authors: Danyeli, Lena Vera, Sen, Zümrüt Duygu, Colic, Lejla, Kurzweil, Lisa, Gensberger-Reigl, Sabrina, Macharadze, Tamar, Götting, Florian, Refisch, Alexander, Liebe, Thomas, Chand, Tara, Kretzschmar, Moritz, Wagner, Gerd, Opel, Nils, Jollant, Fabrice, Speck, Oliver, Munk, Matthias H. J., Li, Meng, Walter, Martin
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 16.02.2023; Nature Publishing Group; Nature Pub. Group
• Subjects: 59/36; 59/57; 631/378; 692/53/2423; Antidepressants; Antidepressive Agents - pharmacology; Behavioral Sciences; Biological Psychology; Glutamic Acid - metabolism; Human health and pathology; Humans; Investigations; Ketamine; Ketamine - pharmacology; Life Sciences; Magnetic Resonance Imaging; Male; Medical imaging; Medicine; Medicine & Public Health; Mental health; Metabolism; Metabolites; Neurobiology; Neuroimaging; Neurosciences; Pharmacotherapy; Psychiatrics and mental health; Psychiatry; Psychotherapy
• ISSN: 2158-3188; 2158-3188
• DOI: 10.1038/s41398-023-02346-0

Ketamine shows rapid antidepressant effects peaking 24 h after administration. The antidepressant effects may occur through changes in glutamatergic metabolite levels and resting-state functional connectivity (rsFC) within the default mode network (DMN). A multistage drug effect of ketamine has been suggested, inducing acute effects on dysfunctional network configuration and delayed effects on homeostatic synaptic plasticity. Whether the DMN-centered delayed antidepressant-related changes are associated with the immediate changes remains unknown. Thirty-five healthy male participants (25.1 ± 4.2 years) underwent 7 T magnetic resonance spectroscopy (MRS) and resting-state functional magnetic resonance imaging (rsfMRI) before, during, and 24 h after a single S-ketamine or placebo infusion. Changes in glutamatergic measures and rsFC in the DMN node pregenual anterior cingulate cortex (pgACC) were examined. A delayed rsFC decrease of the pgACC to inferior parietal lobe (family-wise error corrected p ( p FWEc ) = 0.018) and dorsolateral prefrontal cortex (PFC; p FWEc  = 0.002) was detected that was preceded by an immediate rsFC increase of the pgACC to medial PFC ( p FWEc  < 0.001) and dorsomedial PFC ( p FWEc  = 0.005). Additionally, the immediate rsFC reconfigurations correlated with the delayed pgACC glutamate (Glu) level increase ( p  = 0.024) after 24 h at trend level ( p  = 0.067). Baseline measures of rsFC and MRS were furthermore associated with the magnitude of the respective delayed changes ( p ’s < 0.05). In contrast, the delayed changes were not associated with acute psychotomimetic side effects or plasma concentrations of ketamine and its metabolites. This multimodal study suggests an association between immediate S-ketamine-induced network effects and delayed brain changes at a time point relevant in its clinical context.