Ketamine-induced reduction in mGluR5 availability is associated with an antidepressant response: an [11C]ABP688 and PET imaging study in depression
Open accessAbstract
The mechanisms of action of the rapid antidepressant effects of ketamine, an N-methyl-D-aspartate glutamate receptor antagonist, have not been fully elucidated. This study examined the effects of ketamine on ligand binding to a metabotropic glutamatergic receptor (mGluR5) in individuals with major depressive disorder (MDD) and healthy controls. Thirteen healthy and 13 MDD nonsmokers participated in two [11 C]ABP688 positron emission tomography (PET) scans on the same day-before and during intravenous ketamine administration-and a third scan 1 day later. At baseline, significantly lower [11 C]ABP688 binding was detected in the MDD as compared with the control group. We observed a significant ketamine-induced reduction in mGluR5 availability (that is, [11 C]ABP688 binding) in both MDD and control subjects (average of 14±9% and 19±22%, respectively; P<0.01 for both), which persisted 24 h later. There were no differences in ketamine-induced changes between MDD and control groups at either time point (P=0.8). A significant reduction in depressive symptoms was observed following ketamine administration in the MDD group (P<0.001), which was associated with the change in binding (P<0.04) immediately after ketamine. We hypothesize that glutamate released after ketamine administration moderates mGluR5 availability; this change appears to be related to antidepressant efficacy. The sustained decrease in binding may reflect prolonged mGluR5 internalization in response to the glutamate surge.
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S-ketamine induces a decrease in mGluR5 availability in both healthy and MDD subjects using PET.
“Interestingly, S-ketamine has been shown to induce a decrease in mGluR5 availability both in healthy and MDD subjects using PET (Esterlis et al., 2018; Holmes et al., 2020; Deschwanden et al., 2011).”
From A single subanaesthetic dose of the rapid-acting antidepressant S-ketamine raises presynaptic SV2A density in limbic regions of the Wistar Kyoto rat model of depression (2024) · cites this paper as Esterlis et al., 2018
Alterations of the postsynaptic receptor mGluR5 have been shown in MDD and other psychiatric disorders.
“Studies have also shown alterations of the postsynaptic receptor mGluR5 within MDD and other psychiatric disorders (Abdallah et al., 2017; Esterlis et al., 2018; Holmes et al., 2020; Deschwanden et al., 2011).”
From A single subanaesthetic dose of the rapid-acting antidepressant S-ketamine raises presynaptic SV2A density in limbic regions of the Wistar Kyoto rat model of depression (2024) · cites this paper as Esterlis et al., 2018
Esterlis et al. reported reduced mGluR5 availability both immediately after and 24 h after ketamine administration in both MDD patients and healthy controls.
“Esterlis et al. reported reduced mGluR5 availability both immediately after and 24 h after ketamine administration in both MDD patients and healthy controls whereas Holmes et al. found reduced mGluR5 availability immediately after ketamine administration in healthy volunteers.”
From A single subanaesthetic dose of the rapid-acting antidepressant S-ketamine raises presynaptic SV2A density in limbic regions of the Wistar Kyoto rat model of depression (2024) · cites this paper as Esterlis et al., 2018
Human PET studies and a postmortem Western blotting study found S-ketamine reduces mGluR5 levels in both healthy and depressed subjects.
“Human PET studies, as well as a postmortem Western blotting study, have found S-ketamine to reduce mGluR5 levels in both healthy and depressed subjects laying the basis for our hypothesis (Esterlis et al., 2018; Holmes et al., 2020; Deschwanden et al., 2011).”
From A single subanaesthetic dose of the rapid-acting antidepressant S-ketamine raises presynaptic SV2A density in limbic regions of the Wistar Kyoto rat model of depression (2024) · cites this paper as Esterlis et al., 2018
Data from human studies, including the authors' group, show ketamine's rapid antidepressant effects even in individuals with treatment-resistant depression.
“data from human studies, including our group [103], show ketamine's rapid antidepressant effects even in individuals with treatment-resistant depression”
From Challenges and rewards of in vivo synaptic density imaging, and its application to the study of depression (2025) · cites this paper as [103]
Although mGlu5 may not be altered in MDD, it may still be an important target for symptom modulation.
“suggesting that although mGlu5 may not be altered in MDD, it may still be an important target for symptom modulation.”
From Challenges and rewards of in vivo synaptic density imaging, and its application to the study of depression (2025) · cites this paper as [172]
Ketamine-induced mGlu5 downregulation was associated with an antidepressant response after a single dose.
“ketamine-induced mGlu5 downregulation was associated with an antidepressant response after a single dose [172]”
From Challenges and rewards of in vivo synaptic density imaging, and its application to the study of depression (2025) · cites this paper as [172]
mGlu5 receptor availability is reduced after a single dose of ketamine in individuals with depression and comparison controls.
“we showed that mGlu5 receptor availability is reduced after a single dose of ketamine in individuals with depression and comparison controls”
From Challenges and rewards of in vivo synaptic density imaging, and its application to the study of depression (2025) · cites this paper as [172]
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References 80 · Cited by 148
Research works printed but not linked: 2
- [55]Chowdhury G Behar K Cho W Thomas M Rothman D Sanacora G 1H-[13C]-nuclear magnetic resonance spectroscopy measures of ketamine's effect on amino acid neurotransmitter metabolism Biol Psychiatry 2012 71 1022 1025 22169441 PMC3660962
- [61]DeLorenzo C Kumar JD Mann J Parsey R In vivo variation in metabotropic glutamate receptor subtype 5 binding using positron emission tomography and [11C]ABP688 Journal of Cerebral Blood Flow & Metabolism 2011 31 2169 2180 21792244 PMC3210337
- Authors
- Esterlis, I., DellaGioia, N., Pietrzak, R. H., Matuskey, D., Nabulsi, N., Abdallah, C. G., Yang, J., Pittenger, C., Sanacora, G., Krystal, J. H., Parsey, R. V., Carson, R. E., & DeLorenzo, C.
- Affiliations
- United States Department of Veterans Affairs (US)
- Yale University (US)
- Stony Brook University (US)
- Corresponding author
- Esterlis, I
- ORCID
- Venue
- Molecular Psychiatry
- Published
- 2017-04-11
- Volume
- 23
- Issue
- 4
- Pages
- 824-832
- ISSN
- 1359-4184 (ISSN-L)
- 1476-5578
- PMC
- PMC5636649
- OpenAlex
- W2607180956
- Cited by
- 148
- References
- 80
- Citations by year
- 2026: 4 · 2025: 20 · 2024: 14 · 2023: 18 · 2022: 18 · 2021: 16 · 2020: 14 · 2019: 17 · 2018: 21 · 2017: 5
- FWCI
- 10.82
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Molecular Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Yale University
- National Institutes of Health (5k23mh101498-05)
- National Institute of Mental Health (K01MH092681, K23MH-101498(, R01MH104512, K01MH091354)
- Topics
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Health Sciences › Medicine › Psychiatry and Mental health › Electroconvulsive Therapy Studies
- Keywords
- ketamine, mGluR5, metabotropic glutamate receptors, major depressive disorder, antidepressant response, [11C]ABP688, receptor availability, glutamate release, receptor internalization, rapid-acting antidepressants, positron emission tomography
- MeSH terms
- Adult, Antidepressive Agents, Brain, Carbon Radioisotopes, Depression, Major Depressive Disorder, Female, Humans, Ketamine, Male, Case-Control Studies, Excitatory Amino Acid Antagonists, Glutamic Acid, Positron-Emission Tomography, Receptor, Metabotropic Glutamate 5
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