Could Glutamatergic Modulation be the Keystone of Durable Change in Treatment-Resistant Depression?

Despite decades of advances in antidepressant development, monoaminergic therapies remain limited by delayed onset, incomplete response, and persistent residual symptoms—leaving many patients with major depressive disorder (MDD), particularly those with treatment-resistant depression (TRD), inadequately treated. The growing recognition of glutamatergic dysregulation as a core component of MDD pathophysiology has catalyzed a new era of therapeutics targeting novel neural circuits and synaptic plasticity mechanisms. This clinically focused session will examine the scientific and translational rationale for targeting the glutamatergic system in MDD. Faculty will review current models of glutamate-mediated neurobiology—including synaptic dysfunction, stress-related neurotoxicity, and impaired neuroplasticity—and discuss how these insights inform emerging treatment targets. Participants will critically evaluate the mechanisms of action and most recent clinical data on approved and investigational glutamatergic treatments, with attention to onset of effect, durability, safety considerations, and applicability in real-world practice. Attendees will gain practical strategies to integrate these therapies into individualized treatment plans, optimize outcomes in TRD, and address persistent unmet needs in patients who have not responded adequately to traditional approaches.

Supported by an educational grant from Johnson & Johnson.