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

The mechanisms of action of the rapid antidepressant effects of ketamine, an NMDA glutamate receptor antagonist, have not been fully elucidated. This study examined 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 thirteen 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 to the control group. We observed a significant ketamine-induced reduction in mGluR5 availability, (i.e. [(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 hours 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 post 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.