title: Ketamine-induced reduction in mGluR5 availability is associated with an antidepressant response: an [11C]ABP688 and PET imaging study in depression.
abstract: 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 [11C]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 [11C]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, [11C]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.
authors.affiliation: Department of Psychiatry, Yale University, New Haven, CT, USA.|U.S. Department of Veterans Affairs National Center for Posttraumatic Stress Disorder, Clinical Neurosciences Division, VA Connecticut Healthcare System, West Haven, CT, USA.
authors.forename: I
authors.initials: I
authors.lastname: Esterlis
authors.affiliation: Department of Psychiatry, Yale University, New Haven, CT, USA.
authors.forename: N
authors.initials: N
authors.lastname: DellaGioia
authors.affiliation: Department of Psychiatry, Yale University, New Haven, CT, USA.|U.S. Department of Veterans Affairs National Center for Posttraumatic Stress Disorder, Clinical Neurosciences Division, VA Connecticut Healthcare System, West Haven, CT, USA.
authors.forename: R H
authors.initials: RH
authors.lastname: Pietrzak
authors.affiliation: Department of Psychiatry, Yale University, New Haven, CT, USA.|Department of Radiology and Biomedical Imaging, Yale University, New Haven, CT, USA.
authors.forename: D
authors.initials: D
authors.lastname: Matuskey
authors.affiliation: Department of Radiology and Biomedical Imaging, Yale University, New Haven, CT, USA.
authors.forename: N
authors.initials: N
authors.lastname: Nabulsi
authors.affiliation: Department of Psychiatry, Yale University, New Haven, CT, USA.|U.S. Department of Veterans Affairs National Center for Posttraumatic Stress Disorder, Clinical Neurosciences Division, VA Connecticut Healthcare System, West Haven, CT, USA.
authors.forename: C G
authors.initials: CG
authors.lastname: Abdallah
authors.affiliation: Department of Preventive Medicine, Stony Brook University, Stony Brook, NY, USA.
authors.forename: J
authors.initials: J
authors.lastname: Yang
authors.affiliation: Department of Psychiatry, Yale University, New Haven, CT, USA.
authors.forename: C
authors.identifier: 0000-0003-2117-9321
authors.initials: C
authors.lastname: Pittenger
authors.affiliation: Department of Psychiatry, Yale University, New Haven, CT, USA.
authors.forename: G
authors.initials: G
authors.lastname: Sanacora
authors.affiliation: Department of Psychiatry, Yale University, New Haven, CT, USA.|U.S. Department of Veterans Affairs National Center for Posttraumatic Stress Disorder, Clinical Neurosciences Division, VA Connecticut Healthcare System, West Haven, CT, USA.|Department of Neuroscience, Yale University, New Haven, CT, USA.
authors.forename: J H
authors.initials: JH
authors.lastname: Krystal
authors.affiliation: Department of Psychiatry, Stony Brook University, Stony Brook, NY, USA.|Department of Biomedical Engineering, Stony Brook University, Stony Brook, NY, USA.|Department of Radiology, Stony Brook University, Stony Brook, NY, USA.
authors.forename: R V
authors.initials: RV
authors.lastname: Parsey
authors.affiliation: Department of Radiology and Biomedical Imaging, Yale University, New Haven, CT, USA.|Department of Biomedical Engineering, Yale University, New Haven, CT, USA.
authors.forename: R E
authors.initials: RE
authors.lastname: Carson
authors.affiliation: Department of Psychiatry, Stony Brook University, Stony Brook, NY, USA.|Department of Biomedical Engineering, Stony Brook University, Stony Brook, NY, USA.
authors.forename: C
authors.initials: C
authors.lastname: DeLorenzo
mesh_terms: D000328:Adult; D000928:Antidepressive Agents / Q000494:pharmacology; D001921:Brain / Q000378:metabolism; D002250:Carbon Radioisotopes; D016022:Case-Control Studies; D003863:Depression / Q000000981:diagnostic imaging*; D003865:Major Depressive Disorder / Q000000981:diagnostic imaging / Q000378:metabolism; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005260:Female; D018698:Glutamic Acid / Q000378:metabolism; D006801:Humans; D007649:Ketamine / Q000378:metabolism* / Q000494:pharmacology; D008297:Male; D049268:Positron-Emission Tomography / Q000379:methods; D064529:Receptor, Metabotropic Glutamate 5 / Q000187:drug effects* / Q000378:metabolism
chemical_list: D000928:Antidepressive Agents; D002250:Carbon Radioisotopes; C000615233:Carbon-11; D018691:Excitatory Amino Acid Antagonists; C578935:GRM5 protein, human; D064529:Receptor, Metabotropic Glutamate 5; D018698:Glutamic Acid; D007649:Ketamine