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

Lena Vera Danyeli (1, 2) , Zümrüt Duygu Sen (1, 2) , Lejla Colic (1) , Lisa Kurzweil (3) , Sabrina Gensberger-Reigl (3) , Tamar M. Macharadze (4, 5, 6) , Florian N. Götting (1) , Alexander Refisch (1) , Thomas Liebe (1) , Tara Chand (1, 2, 7) , Moritz A. Kretzschmar (4) , Gerd Wagner (1) , Nils Opel (1) , Fabrice Jollant (8, 1, 9, 10, 11) , Oliver Speck (6, 5, 4) , M. H. Munk (2, 12) , Meng Li (1) , Martin Walter (1, 2, 6, 5, 13)

1 Jena University Hospital [Jena]
2 University of Tübingen
3 FAU - Friedrich-Alexander Universität Erlangen-Nürnberg = University of Erlangen-Nuremberg
4 OVGU - Otto-von-Guericke-Universität Magdeburg = Otto-von-Guericke University [Magdeburg]
5 LIN - Leibniz Institute for Neurobiology [Magdeburg]
6 Center for Behavioral Brain Sciences, Magdeburg, Germany
7 Friedrich-Schiller-Universität = Friedrich Schiller University Jena [Jena, Germany]
8 CESP - Centre de recherche en épidémiologie et santé des populations
9 Hôpital Bicêtre [AP-HP, Le Kremlin-Bicêtre]
10 CHU Nîmes - Centre Hospitalier Universitaire de Nîmes
11 McGill University = Université McGill [Montréal, Canada]
12 Darmstadt University of Technology [Darmstadt]
13 Max Planck Institute for Biological Cybernetics

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 (pFWEc) = 0.018) and dorsolateral prefrontal cortex (PFC; pFWEc = 0.002) was detected that was preceded by an immediate rsFC increase of the pgACC to medial PFC (pFWEc < 0.001) and dorsomedial PFC (pFWEc = 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.

Domaines: Psychiatrie et santé mentale

Lena Vera Danyeli, Zümrüt Duygu Sen, Lejla Colic, Lisa Kurzweil, Sabrina Gensberger-Reigl, et al.. Association of the delayed changes in glutamate levels and functional connectivity with the immediate network effects of S-ketamine. Translational Psychiatry, 2023, 13 (1), ⟨10.1038/s41398-023-02346-0⟩. ⟨hal-04106284⟩