Association of the delayed changes in glutamate levels and functional connectivity with the immediate network effects of S-ketamine
Lena Vera Danyeli, Zümrüt Duygu Sen, Lejla Colic, Lisa Kurzweil, Sabrina Gensberger‐Reigl, Tamar Macharadze, Florian N. Götting, Alexander Refisch, Thomas Liebe, Tara Chand, Moritz Kretzschmar, Gerd Wagner, Nils Opel, Fabrice Jollant, Oliver Speck, Matthias H. J. Munk, Meng Li, Martin Walter
Translational Psychiatry February 16, 2023 DOI: 10.1038/s41398-023-02346-0 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Randomized, placebo-controlled, within-subject multimodal neuroimaging study Peer reviewed |
|---|---|
| Sample size | 35 |
| Population | Healthy male participants (mean age 25.1 ± 4.2 years) |
| Intervention | S-ketamine |
| Duration | Single infusion, assessments before, during, and 24 hours after |
| Measures | 7 T magnetic resonance spectroscopy (MRS), resting-state functional magnetic resonance imaging (rsfMRI) |
| Topics | Esketamine Ketamine |
| Citations | 15 |
| Key points | A single S-ketamine infusion caused an immediate increase in pgACC connectivity to medial and dorsomedial prefrontal cortex, followed by a delayed decrease in pgACC connectivity to inferior parietal lobe and dorsolateral prefrontal cortex at 24 hours. The immediate connectivity changes correlated with the delayed pgACC glutamate increase at a trend level. Baseline connectivity and metabolite levels were associated with the magnitude of delayed changes, while delayed changes were not associated with acute psychotomimetic effects or plasma ketamine/metabolite concentrations. |
Abstract
Abstract 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.