Ketamine-induced reduction in mGluR5 availability is associated with an antidepressant response: an [11C]ABP688 and PET imaging study in depression

• Published in: Molecular psychiatry Vol. 23; no. 4; pp. 824 - 832
• Main 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
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.04.2018; Nature Publishing Group
• Subjects: 631/337; 631/378; Adult; Antidepressants; Antidepressive Agents - pharmacology; Anxiety disorders; Behavioral Sciences; Biological Psychology; Biomedical engineering; Brain - metabolism; Carbon Radioisotopes; Case-Control Studies; Comparative analysis; Depression - diagnostic imaging; Depressive Disorder, Major - diagnostic imaging; Depressive Disorder, Major - metabolism; Dosage and administration; Drug abuse; Excitatory Amino Acid Antagonists - pharmacology; Female; Glutamatergic transmission; Glutamic Acid - metabolism; Glutamic acid receptors (metabotropic); Health care; Humans; Internalization; Intravenous administration; Ketamine; Ketamine - metabolism; Ketamine - pharmacology; Ligands; Major depressive disorder; Male; Medicine; Medicine & Public Health; Mental depression; Mental disorders; Metabotropic glutamate receptors; Metabotropic receptors; N-Methyl-D-aspartic acid receptors; Neurosciences; original-article; Pharmacotherapy; Positron emission tomography; Positron-Emission Tomography - methods; Proteins; Psychiatry; Radiation; Receptor, Metabotropic Glutamate 5 - drug effects; Receptor, Metabotropic Glutamate 5 - metabolism; Spectrum analysis; Substance abuse treatment; Tomography
• ISSN: 1359-4184; 1476-5578
• DOI: 10.1038/mp.2017.58

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.