704. Targeting the Glutamatergic System: Novel Therapeutics in Unipolar and Bipolar Depression

Abstract

Abstract Background Glutamatergic dysfunction is increasingly recognized as a core mechanism in both unipolar and bipolar depression, contributing to impaired neuroplasticity, disrupted excitatory–inhibitory balance, and treatment resistance. Emerging therapies that modulate glutamate pathways—particularly NMDA receptor antagonists, AMPA-mediated mechanisms, and metabotropic glutamate receptor modulators—offer rapid and clinically meaningful antidepressant effects. Aims & Objectives To review current evidence for the efficacy of glutamate acting treatments in unipolar and bipolar depression and to identify future prospects. Method Narrative review. Results Agents such as ketamine and esketamine demonstrate the potential of restoring synaptic function through glutamate-driven mechanisms, while newer compounds aim to achieve similar benefits with improved safety and sustained efficacy. Evidence from translational research and clinical trials highlights shared mechanistic pathways across mood disorders, though bipolar depression poses specific challenges related to mood instability and long-term management. Discussion & Conclusions This presentation will synthesize current knowledge on glutamatergic targets, discuss biomarkers and patient-selection strategies, and outline future directions for integrating these therapies into treatment pathways for mood disorders.