Depression and antidepressant efficacy

In work related to understanding the pathophysiology of depression and its treatment, we are investigating the role of neurotrophins, in particular brain-derived neurotrophic factor (BDNF), and their receptors in adult brain function using conditional and inducible, cell-type-specific knockout mice. Our work has established a critical role for BDNF in determining antidepressant efficacy as well as certain aspects of depressive-like behavior. Specifically, our research has demonstrated that BDNF selectively in the hippocampus dentate gyrus is necessary to mediate antidepressant responses in rodent models.

More recently, we have been investigating the mechanism underlying the efficacy of fast-acting antidepressants. In recent work we have shown that ketamine-mediated NMDA receptor blockade at rest deactivates eukaryotic elongation factor 2 (eEF2) kinase resulting in a reduction of eEF2 phosphorylation and de-suppression of BDNF translation that is necessary for rapid behavioral antidepressant responses. Our data supports the novel hypothesis that ketamine-mediated block of spontaneous NMDA receptor mediated transmission at rest is necessary and sufficient to elicit a rapid antidepressant effect. This hypothesis can also explain clinical data on why memantine, a clinically used NMDA receptor antagonist, is not effect as a rapid antidepressant.