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Mol Psychiatry. 2018 Apr;23(4):824-832. doi: 10.1038/mp.2017.58. Epub 2017 Apr 11.

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

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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 Radiology and Biomedical Imaging, Yale University, New Haven, CT, USA.
Department of Preventive Medicine, Stony Brook University, Stony Brook, NY, USA.
Department of Neuroscience, Yale University, New Haven, CT, USA.
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.
Department of Biomedical Engineering, Yale University, New Haven, CT, USA.


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.

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