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

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.

Neural connectivity moderators and mechanisms of ketamine treatment among treatment-resistant depressed patients: a randomized controlled trial

“… 26 Our findings related to the dmPFC are consistent with the animal literature, which finds effects of ketamine in enhancing neuronal connectivity from the PFC and clinical literature identifying the dmPFC as a region greatly impacted by ketamine treatment. 27 , 28 Overall, our findings appear convergent with the strong pre-clinical literature that identifies increases in synaptic plasticity in the PFC as a prominent mechanism of ketamine's therapeutic action, validating key associations from these animal models within a comparatively large sample of TRD patients using a randomized design to separate ketamine-specific from non-specific patterns. 9 …”

Esketamine: Less Drowsiness, More Analgesia

“…In addition to immediate effects, racemic ketamine and esketamine induced delayed changes in resting state functional connectivity within the brain’s default mode network (DMN) as shown in magnetic resonance imaging (MRI) investigation. 24,114 The delayed effects can be seen 24 hours after 1 subanesthetic drug dose (0.11 mg/kg bolus administered over 2 minutes followed by 0.22 mg.kg –1 .h –1 infusion over 40 minutes). Although data gained in healthy volunteers likely do not fully depict the situation in postsurgical pain patients, it has to be noted that the delayed neuroimaging changes manifested without any psychedelic symptoms and without esketamine and nor-/ hydroxynor-ketamine metabolite plasma levels.…”