Skip to content

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)

The journal has published a correction to this paper. Read the correction (opens in new tab)

Read Full Text
Relevant Not relevant

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.

Comparable studies

Other randomized controlled trials on esketamine, most cited first.

Study Year Design Participants
Efficacy and Safety of Flexibly Dosed Esketamine Nasal Spray Combined With a Newly Initiated Oral Antidepressant in Treatment-Resistant Depression: A Randomized Double-Blind Active-Controlled Study Adults with moderate to severe nonpsychotic depression and a history of nonresponse to... 2019 Phase 3, double-blind, active-controlled, multicenter randomized controlled trial n = 227
Efficacy of Esketamine Nasal Spray Plus Oral Antidepressant Treatment for Relapse Prevention in Patients With Treatment-Resistant Depression Adults with treatment-resistant depression who achieved stable remission or stable... 2019 Phase 3, multicenter, double-blind, randomized withdrawal study n = 297
Efficacy and Safety of Intranasal Esketamine Adjunctive to Oral Antidepressant Therapy in Treatment-Resistant Depression Adults with DSM-IV-TR diagnosis of major depressive disorder and history of inadequate... 2017 Phase 2, double-blind, doubly randomized, delayed-start, placebo-controlled study n = 67
Efficacy and Safety of Intranasal Esketamine for the Rapid Reduction of Symptoms of Depression and Suicidality in Patients at Imminent Risk for Suicide: Results of a Double-Blind, Randomized, Placebo-Controlled Study Depressed patients at imminent risk for suicide 2018 Randomized controlled trial n = 68
Efficacy and Safety of Fixed-Dose Esketamine Nasal Spray Combined With a New Oral Antidepressant in Treatment-Resistant Depression: Results of a Randomized, Double-Blind, Active-Controlled Study (TRANSFORM-1) Adults with moderate-to-severe depression and nonresponse to at least two... 2019 Randomized controlled trial n = 346

Citations in the library

Cited by 6

and 1 more in the library

Cites 29

and 24 more in the library

Related reading

Explore topics

Esketamine Ketamine Default mode network Neuroplasticity