PMID- 36797238 OWN - NLM STAT- MEDLINE DCOM- 20230222 LR - 20230328 IS - 2158-3188 (Electronic) IS - 2158-3188 (Linking) VI - 13 IP - 1 DP - 2023 Feb 16 TI - Association of the delayed changes in glutamate levels and functional connectivity with the immediate network effects of S-ketamine. PG - 60 LID - 10.1038/s41398-023-02346-0 [doi] LID - 60 AB - 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. CI - (c) 2023. The Author(s). FAU - Danyeli, Lena Vera AU - Danyeli LV AD - Department of Psychiatry and Psychotherapy, Jena University Hospital, Jena, Germany. AD - Clinical Affective Neuroimaging Laboratory (CANLAB), Magdeburg, Germany. AD - Department of Psychiatry and Psychotherapy, University Tubingen, Tubingen, Germany. FAU - Sen, Zumrut Duygu AU - Sen ZD AD - Department of Psychiatry and Psychotherapy, Jena University Hospital, Jena, Germany. AD - Clinical Affective Neuroimaging Laboratory (CANLAB), Magdeburg, Germany. AD - Department of Psychiatry and Psychotherapy, University Tubingen, Tubingen, Germany. AD - Center for Intervention and Research on adaptive and maladaptive brain Circuits underlying mental health (C-I-R-C), Jena-Magdeburg-Halle, Germany. FAU - Colic, Lejla AU - Colic L AD - Department of Psychiatry and Psychotherapy, Jena University Hospital, Jena, Germany. AD - Clinical Affective Neuroimaging Laboratory (CANLAB), Magdeburg, Germany. AD - Center for Intervention and Research on adaptive and maladaptive brain Circuits underlying mental health (C-I-R-C), Jena-Magdeburg-Halle, Germany. AD - German Center for Mental Health (DZPG), Site Halle-Jena-Magdeburg, Germany. FAU - Kurzweil, Lisa AU - Kurzweil L AD - Food Chemistry, Department of Chemistry and Pharmacy, Friedrich-Alexander-Universitat Erlangen-Nurnberg, Erlangen, Germany. FAU - Gensberger-Reigl, Sabrina AU - Gensberger-Reigl S AUID- ORCID: 0000-0001-5104-9603 AD - Food Chemistry, Department of Chemistry and Pharmacy, Friedrich-Alexander-Universitat Erlangen-Nurnberg, Erlangen, Germany. FAU - Macharadze, Tamar AU - Macharadze T AD - Department of Anesthesiology and Intensive Care Medicine, Medical Faculty, Otto-von-Guericke-Universitat Magdeburg, Magdeburg, Germany. AD - Department Systems Physiology of Learning, Leibniz Institute for Neurobiology, Magdeburg, Germany. AD - Center for Behavioral Brain Sciences, Magdeburg, Germany. FAU - Gotting, Florian AU - Gotting F AUID- ORCID: 0000-0002-4800-9931 AD - Department of Psychiatry and Psychotherapy, Jena University Hospital, Jena, Germany. AD - Clinical Affective Neuroimaging Laboratory (CANLAB), Magdeburg, Germany. FAU - Refisch, Alexander AU - Refisch A AUID- ORCID: 0000-0002-3505-1575 AD - Department of Psychiatry and Psychotherapy, Jena University Hospital, Jena, Germany. FAU - Liebe, Thomas AU - Liebe T AD - Department of Psychiatry and Psychotherapy, Jena University Hospital, Jena, Germany. AD - Clinical Affective Neuroimaging Laboratory (CANLAB), Magdeburg, Germany. FAU - Chand, Tara AU - Chand T AD - Department of Psychiatry and Psychotherapy, Jena University Hospital, Jena, Germany. AD - Clinical Affective Neuroimaging Laboratory (CANLAB), Magdeburg, Germany. AD - Department of Psychiatry and Psychotherapy, University Tubingen, Tubingen, Germany. AD - Department of Clinical Psychology, Friedrich Schiller University, Jena, Germany. FAU - Kretzschmar, Moritz AU - Kretzschmar M AUID- ORCID: 0000-0002-5285-2737 AD - Department of Anesthesiology and Intensive Care Medicine, Medical Faculty, Otto-von-Guericke-Universitat Magdeburg, Magdeburg, Germany. FAU - Wagner, Gerd AU - Wagner G AUID- ORCID: 0000-0003-2296-0259 AD - Department of Psychiatry and Psychotherapy, Jena University Hospital, Jena, Germany. AD - Center for Intervention and Research on adaptive and maladaptive brain Circuits underlying mental health (C-I-R-C), Jena-Magdeburg-Halle, Germany. FAU - Opel, Nils AU - Opel N AUID- ORCID: 0000-0003-4749-3298 AD - Department of Psychiatry and Psychotherapy, Jena University Hospital, Jena, Germany. AD - Center for Intervention and Research on adaptive and maladaptive brain Circuits underlying mental health (C-I-R-C), Jena-Magdeburg-Halle, Germany. AD - German Center for Mental Health (DZPG), Site Halle-Jena-Magdeburg, Germany. FAU - Jollant, Fabrice AU - Jollant F AD - Department of Psychiatry and Psychotherapy, Jena University Hospital, Jena, Germany. AD - School of Medicine, Universite Paris-Saclay, Le Kremlin-Bicetre, France. AD - Department of psychiatry, CHU Bicetre, APHP, Le Kremlin-Bicetre, France. AD - Inserm, CESP, MOODS team, Le Kremlin-Bicetre, France. AD - Department of psychiatry, CHU Nimes, Nimes, France. AD - Department of Psychiatry, McGill University, Montreal, Canada. FAU - Speck, Oliver AU - Speck O AD - Center for Intervention and Research on adaptive and maladaptive brain Circuits underlying mental health (C-I-R-C), Jena-Magdeburg-Halle, Germany. AD - German Center for Mental Health (DZPG), Site Halle-Jena-Magdeburg, Germany. AD - Center for Behavioral Brain Sciences, Magdeburg, Germany. AD - Department of Behavioral Neurology, Leibniz Institute for Neurobiology, Magdeburg, Germany. AD - Department of Biomedical Magnetic Resonance, Otto von Guericke University, Magdeburg, Germany. FAU - Munk, Matthias H J AU - Munk MHJ AD - Department of Psychiatry and Psychotherapy, University Tubingen, Tubingen, Germany. AD - Systems Neurophysiology, Department of Biology, Darmstadt University of Technology, Darmstadt, Germany. FAU - Li, Meng AU - Li M AD - Department of Psychiatry and Psychotherapy, Jena University Hospital, Jena, Germany. Meng.Li@med.uni-jena.de. AD - Clinical Affective Neuroimaging Laboratory (CANLAB), Magdeburg, Germany. Meng.Li@med.uni-jena.de. AD - Center for Intervention and Research on adaptive and maladaptive brain Circuits underlying mental health (C-I-R-C), Jena-Magdeburg-Halle, Germany. Meng.Li@med.uni-jena.de. FAU - Walter, Martin AU - Walter M AUID- ORCID: 0000-0001-7857-4483 AD - Department of Psychiatry and Psychotherapy, Jena University Hospital, Jena, Germany. Martin.Walter@med.uni-jena.de. AD - Clinical Affective Neuroimaging Laboratory (CANLAB), Magdeburg, Germany. Martin.Walter@med.uni-jena.de. AD - Department of Psychiatry and Psychotherapy, University Tubingen, Tubingen, Germany. Martin.Walter@med.uni-jena.de. AD - Center for Intervention and Research on adaptive and maladaptive brain Circuits underlying mental health (C-I-R-C), Jena-Magdeburg-Halle, Germany. Martin.Walter@med.uni-jena.de. AD - German Center for Mental Health (DZPG), Site Halle-Jena-Magdeburg, Germany. Martin.Walter@med.uni-jena.de. AD - Center for Behavioral Brain Sciences, Magdeburg, Germany. Martin.Walter@med.uni-jena.de. AD - Department of Behavioral Neurology, Leibniz Institute for Neurobiology, Magdeburg, Germany. Martin.Walter@med.uni-jena.de. AD - Max Planck Institute for Biological Cybernetics, Tubingen, Germany. Martin.Walter@med.uni-jena.de. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20230216 PL - United States TA - Transl Psychiatry JT - Translational psychiatry JID - 101562664 RN - 50LFG02TXD (Esketamine) RN - 690G0D6V8H (Ketamine) RN - 3KX376GY7L (Glutamic Acid) RN - 0 (Antidepressive Agents) SB - IM EIN - Transl Psychiatry. 2023 Feb 28;13(1):73. PMID: 36854748 MH - Humans MH - Male MH - *Ketamine/pharmacology MH - Glutamic Acid/metabolism MH - Magnetic Resonance Imaging MH - Antidepressive Agents/pharmacology PMC - PMC9935558 COIS- MW is a member of the following advisory boards and gave presentations to the following companies: Bayer AG, Germany; Boehringer Ingelheim, Germany; and Biologische Heilmittel Heel GmbH, Germany. MW has further conducted studies with institutional research support from HEEL and Janssen Pharmaceutical Research for a clinical trial (IIT) on ketamine in patients with MDD, unrelated to this investigation. MW did not receive any financial compensation from the companies mentioned above. All other authors report no biomedical financial interests or other potential conflicts of interest. EDAT- 2023/02/17 06:00 MHDA- 2023/02/22 06:00 PMCR- 2023/02/16 CRDT- 2023/02/16 23:13 PHST- 2022/06/30 00:00 [received] PHST- 2023/01/30 00:00 [accepted] PHST- 2023/01/20 00:00 [revised] PHST- 2023/02/16 23:13 [entrez] PHST- 2023/02/17 06:00 [pubmed] PHST- 2023/02/22 06:00 [medline] PHST- 2023/02/16 00:00 [pmc-release] AID - 10.1038/s41398-023-02346-0 [pii] AID - 2346 [pii] AID - 10.1038/s41398-023-02346-0 [doi] PST - epublish SO - Transl Psychiatry. 2023 Feb 16;13(1):60. doi: 10.1038/s41398-023-02346-0.